CN114544842B - Method for detecting N-bromosuccinimide in voriconazole - Google Patents
Method for detecting N-bromosuccinimide in voriconazole Download PDFInfo
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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
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- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
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Abstract
The invention provides a method for detecting N-bromosuccinimide in voriconazole, wherein the N-bromosuccinimide is a material used in the voriconazole synthesis process and possibly remains in a voriconazole finished product, and the method is researched for detecting the N-bromosuccinimide in the voriconazole in order to control the content of the N-bromosuccinimide in the voriconazole finished product; the method is implemented using LC-MS detection, which is validated with reference to the ICH Q2 guidelines in order to validate the validity and feasibility of the method. The method is simple to operate, consumes less time, can obtain accurate and effective data, has higher system applicability, and meets the standards in specificity, precision, accuracy, linearity, range and durability.
Description
Technical Field
The invention relates to the technical field of medical analysis, in particular to a method for detecting N-bromosuccinimide in voriconazole.
Background
Voriconazole is first marketed in the united states in 2002, is a product of further structural modification of fluconazole, belongs to a third-generation triazole antifungal drug, has the characteristics of wide antibacterial spectrum, high bioavailability, safety, wide tissue distribution, capability of passing through blood brain barrier and the like, increases the clinical dosage year by year, has better antibacterial activity on candida, cryptococcus, aspergillus and the like, has better curative effect on aspergillus fumigatus infection which is difficult to treat clinically, has the same curative effect on aspergillus and amphotericin B, is the first choice for treating pulmonary aspergillosis in guidelines, and is also an empirical therapeutic drug for patients with neutrophil reduction fever. Voriconazole is metabolized in the human body mainly through CYP2C19 enzyme, and because of the polymorphism of CYP2C19 gene, the action mechanism is to inhibit fungal 14-alpha-sterol demethylase competitively, so that the biosynthesis of ergosterol (converted by lanosterol) which is an important component of a cell membrane is blocked, the fluidity and permeability of the cell membrane and the activities of a plurality of enzymes on the cell membrane are influenced, and the antifungal effect is exerted.
N-bromosuccinimide is a material used in the voriconazole synthesis process, possibly remains in the voriconazole finished product, and in order to control the content of the N-bromosuccinimide in the voriconazole finished product, research and development personnel conduct method research on the detection of the N-bromosuccinimide in the voriconazole; the invention provides a method for detecting N-bromosuccinimide in voriconazole for the first time, which is realized by using LC-MS detection, and in order to verify the validity and feasibility of the method, the method is verified by referring to ICH Q2 guiding principle.
Disclosure of Invention
The invention aims to provide a method for detecting N-bromosuccinimide in voriconazole, which is simple, efficient and accurate, can shorten the detection time to achieve higher efficiency on the premise of not influencing the detection result, and can be used for quality control of voriconazole bulk drug by verifying the method with reference to ICH Q2 guiding principle.
In order to achieve the above object, the present invention provides the following technical solutions:
the method for detecting the N-bromosuccinimide in the voriconazole comprises the following steps of: (1) Preparing solutions, namely preparing a blank solution, a reference stock solution, a reference solution, a sensitivity solution and a test solution respectively; the blank solution is a diluent 1 and a diluent 2; the control stock solution and the control solution comprise N-bromosuccinimide, a diluent 1 and a diluent 2; the sensitivity solution comprises N-bromosuccinimide, a diluent 1 and a diluent 2; the sample solution comprises voriconazole, a diluent 1 and a diluent 2;
(2) The measuring method comprises the following steps: respectively injecting a blank solution, a sensitivity solution, a reference substance solution and a test sample solution into a liquid chromatograph, recording a chromatogram, and performing chromatographic conditions as follows: chromatographic column: octadecylsilane chemically bonded silica is used as a filler; sample injection amount: 20 μl; column temperature: 30 ℃; flow rate: 0.4ml/min; the eluent is a mobile phase A-mobile phase B system; mobile phase a was 10mM ammonium acetate solution (containing 0.1% glacial acetic acid); the mobile phase B is: acetonitrile;
the gradients of mobile phase a and mobile phase B are shown below:
the ion source parameters are as follows:
further, the preparation steps of the blank solution are as follows: blank solution is diluent 1 and diluent 2, wherein diluent 1 is acetonitrile: acetone=1:1 (V/V, volume ratio), the diluent 2 being water;
the preparation steps of the reference substance stock solution are as follows: taking an N-bromosuccinimide reference substance, precisely weighing, placing in a volumetric flask, adding a diluent 1 for dissolution, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a volumetric flask, adding the diluent 2 to dilute to a scale, and shaking to obtain a reference stock solution;
the preparation steps of the reference substance solution are as follows: precisely measuring the reference stock solution, placing in a volumetric flask, adding the diluent 1, diluting to scale, and shaking; precisely measuring the solution, placing in a volumetric flask, adding diluent 2, diluting to scale, and shaking to obtain reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring the reference substance solution, placing in a volumetric flask, adding blank solution, diluting to scale, and shaking to obtain sensitivity solution;
the preparation steps of the sample solution are as follows: taking a sample, precisely weighing, placing in a volumetric flask, adding the diluent 1, performing ultrasonic dissolution, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a volumetric flask, adding diluent 2, diluting to scale, shaking to precipitate sample, and filtering with a filter membrane to obtain sample solution;
the glacial acetic acid and ammonium acetate are AR and above;
the acetonitrile, ultrapure water and acetone are HPLC;
the N-bromosuccinimide reference substance is purchased outsourced;
the chromatographic column may be a Thermo Acclaim TM 120 A C18 120 a 4.6x150mm, 5 μm, or a chromatographic column of comparable potency.
The method for measuring the content of the N-bromosuccinimide further comprises a method verification before detection, wherein the method verification is carried out according to the chromatographic conditions of formal detection, and the measurement result is as follows:
advantageous effects
According to the technical scheme, the detection method disclosed by the invention has high chromatographic peak separation degree of N-bromosuccinimide in voriconazole and higher system applicability, and meets the standards in terms of specificity, precision, quantitative limit, detection limit, accuracy, linearity, range and durability. In order to confirm the residual quantity of N-bromosuccinimide in voriconazole, the invention utilizes a convenient and quick liquid chromatography-mass spectrometry method, and verifies the method for proving the effectiveness and feasibility of the method. The detection of N-bromosuccinimide in voriconazole can be used for monitoring the quality of voriconazole bulk drug and preparation. The invention provides a method for detecting N-bromosuccinimide in voriconazole by using a gas chromatography-mass spectrometry method for the first time, and has the characteristics of high accuracy, high precision, good repeatability, good stability, strong specificity and the like.
Drawings
FIG. 1 is a liquid chromatogram of a hollow white solution of examples 2, 3, 4, 5;
FIG. 2 is a liquid chromatogram of the sensitivity solution in examples 2 and 5;
FIG. 3 is a liquid chromatogram of the control solution in examples 2, 3, and 4;
FIG. 4 is a liquid chromatogram of the sample solution in example 3;
FIG. 5 is a liquid chromatogram of the selective solution of example 3;
FIG. 6 is a liquid chromatogram of the sample solution (labeled) of example 4;
FIG. 7 is a liquid chromatogram of the LOQ solution of example 5;
FIG. 8 is a liquid chromatogram of the LOD solution of example 5;
FIG. 9 is a linear relationship of N-bromosuccinimide.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
(1) Experimental materials and instrument conditions
Experimental materials: acetonitrile, manufacturer: merck; glacial acetic acid, manufacturer: guangdong Guanghua technology, inc.; ammonium acetate, manufacturer: sigma-aldrich; acetone, manufacturer: west Long science Co., ltd; n-bromosuccinimide, manufacturer: shanghai Miclin Biochemical technologies Co., ltd; voriconazole, manufacturer: zhuhai Ruodu pharmaceutical Co., ltd; water, manufacturer: watson.
Instrument: liquid chromatograph mass spectrometer: agilent Infinity 1290 UHPLC+Agilent 6470QQQ-MS; electronic analytical balance (XSE 205DU, ME 204E); chromatographic column: acclaim TM 120 C18 120A 4.6×150mm，5µm。
Respectively injecting a blank solution, a sensitivity solution, a reference substance solution and a test sample solution into a liquid chromatograph, recording a chromatogram, and performing chromatographic conditions as follows: chromatographic column: octadecylsilane chemically bonded silica is used as a filler; sample injection amount: 20 μl; column temperature: 30 ℃; flow rate: 0.4ml/min; the eluent is a mobile phase A-mobile phase B system; mobile phase a was 10mM ammonium acetate solution (containing 0.1% glacial acetic acid); the mobile phase B is: acetonitrile;
the gradients of mobile phase a and mobile phase B are shown below:
the ion source parameters are as follows:
(2) Experimental procedure
(1) Preparation of a blank solution: taking a 20ml volumetric flask, adding 8ml of diluent 1, adding diluent 2, diluting to scale, and shaking to obtain an empty solution;
(2) preparation of control stock solution: taking about 21mg of N-bromosuccinimide reference substance, precisely weighing, placing into a 20ml volumetric flask, adding the diluent 1 to dissolve and dilute to scale, and shaking uniformly; precisely measuring 250 μl of the above solution, placing in a 100ml volumetric flask, adding diluent 1, diluting to scale, and shaking to obtain reference stock solution (concentration: 2.625 μg/ml);
(3) preparation of control solution (N-bromosuccinimide positioning solution): precisely measuring 1.0ml of reference stock solution, placing into a 5ml volumetric flask, adding the diluent 1 to dilute to scale, and shaking; precisely measuring 4.0ml of the solution, placing in a 10ml volumetric flask, adding the diluent 2 to dilute to a scale, and shaking uniformly to obtain a reference solution (concentration: 210 ng/ml);
(4) preparation of a sensitivity solution: precisely measuring 5.0ml of reference substance solution, placing in a 10ml volumetric flask, adding blank solution to dilute to scale, and shaking to obtain sensitivity solution (concentration: 105 ng/ml);
(5) preparation of test solution (voriconazole positioning solution): taking about 1.4g of a sample to be tested, precisely weighing, placing the sample into a 5ml volumetric flask, adding the diluent 1, carrying out ultrasonic dissolution, diluting to a scale, and shaking uniformly; precisely measuring 4.0ml of the solution, placing in a 10ml volumetric flask, adding diluent 2, diluting to scale, shaking, precipitating sample, and filtering with 0.22 μm filter membrane to obtain sample solution (concentration: 112 mg/ml);
(6) preparation of the selective solution: taking about 1.4g of a sample to be tested, precisely weighing, placing in a 5ml volumetric flask, precisely weighing 1.0ml of a reference substance stock solution, placing in the volumetric flask, adding the diluent 1, ultrasonically dissolving, diluting to a scale, and shaking uniformly; precisely measuring 4.0ml of the solution, placing the solution into a 10ml volumetric flask, adding the diluent 2 to dilute to a scale, shaking uniformly to separate out a sample, and filtering with a 0.22 mu m filter membrane to obtain a selective solution (the concentration is 112mg/ml of voriconazole and 210ng/ml of N-bromosuccinimide);
(7) preparation of test solution (labeled): taking about 1.4g of a sample to be tested, precisely weighing, placing in a 5ml volumetric flask, precisely weighing 1.0ml of a reference substance stock solution, placing in the volumetric flask, adding the diluent 1, ultrasonically dissolving, diluting to a scale, and shaking uniformly; precisely measuring 4.0ml of the solution, placing in a 10ml volumetric flask, adding diluent 2 to dilute to scale, shaking uniformly to precipitate a sample, and filtering with a 0.22 μm filter membrane to obtain a sample solution (with standard) (concentration: voriconazole 112mg/ml, N-bromosuccinimide 210 ng/ml);
(8) preparation of LOQ solution: according to the S/N value of the N-bromosuccinimide obtained by the sensitivity solution, the dilution ratio is adjusted to be not less than 10. 6 parts of the mixture were prepared in the same manner.
(9) Preparation of LOD solution: 3.0ml of LOQ solution is precisely measured, placed in a 10ml volumetric flask, added with blank solution to dilute to scale, and shaken well to obtain LOD solution.
After the system is stable, a blank solution 1 needle, a sensitivity solution 1 needle, a reference solution 6 needle are added, and a chromatogram is recorded.
Example 2 System applicability test of the detection method according to the invention
The system applicability is achieved by measuring the S/N value of N-bromosuccinimide in a sensitivity solution and RSD of the peak area of N-bromosuccinimide in a 6-needle reference solution. The S/N value of the N-bromosuccinimide in the sensitivity solution is required to be more than or equal to 10; the RSD of the peak area of the N-bromosuccinimide in the 6-needle reference solution is not more than 10.0%. To confirm the system applicability during the sequence operation, 1 needle of control solution is added every 8 hours and at the end of the sequence in the verification process, and the RSD of the peak area of N-bromosuccinimide in the 6 consecutive needle of control solution is required to be not more than 10.0%; if the range is out, an evaluation investigation should be made.
Preparing a blank solution, a sensitivity solution and a reference substance solution according to the method in the embodiment 1, feeding the blank solution 1 needle, the sensitivity solution 1 needle and the reference substance solution 6 needle under the chromatographic conditions in the embodiment 1 to obtain chromatograms, as shown in fig. 1, 2 and 3, and converting the results according to the formula as shown in the following table:
example 3A test method specific to the detection method according to the invention
The specificity of the method is that the blank solution is measured to have no interference on detection; the separation degree between N-bromosuccinimide and adjacent peaks in the selective solution is realized, the blank solution is required to have no interference to detection, and the separation degree between N-bromosuccinimide and adjacent peaks in the selective solution is required to be not less than 1.5.
Preparing a blank solution, a reference solution, a test solution and a selective solution according to the embodiment 1, and feeding a blank solution 1 needle, a reference solution 1 needle, a test solution 1 needle and a selective solution 1 needle under the chromatographic conditions described in the embodiment 1 to obtain chromatograms, wherein the chromatograms are shown in the following table according to the conversion results of formulas in fig. 1, 3, 4 and 5:
example 4 precision test of the detection method according to the invention
Repeatability is achieved by testing the RSD of the assay result for 6 parts of the test solution (labeled), requiring that the RSD of the assay result for N-bromosuccinimide in 6 parts of the test solution (labeled) should be no greater than 10.0%.
Preparing a blank solution, a reference solution and a test solution (labeled) according to the embodiment 1, after the system is balanced, feeding 1 needle of the blank solution, 6 needles of the reference solution, 1 needle of the blank solution and 1 needle of the test solution (labeled) respectively, recording chromatograms, and obtaining the specific detection results as follows:
example 5 quantitative limit and detection limit of the detection method of the present invention
The quantitative limit and the detection limit are realized by detecting the ratio of the response signal to the noise, and the signal-to-noise ratio (S/N) of the quantitative limit should be not less than 10:1, the signal to noise ratio (S/N) of the detection limit should be not less than 3:1, a step of; at the quantitative concentration limiting level, repeatedly examining 6 parts of quantitative limiting solution, wherein the RSD of the unit concentration peak area of the N-bromosuccinimide in 6 parts of LOQ solution is required to be not more than 20.0%; LOQN-bromosuccinimide should not more than 0.9ppm, S/N is not less than 10; the S/N of the N-bromosuccinimide in the LOD solution is more than or equal to 3, and the LOD is less than LOQ.
Blank solution, sensitivity solution, LOQ solution and LOD solution were prepared as described in example 1. After the system was equilibrated, 1 needle of blank solution, 1 needle of sensitivity solution, 6 portions of LOQ solution each, 1 needle of LOD solution, and 1 needle of LOD solution were entered and chromatograms were recorded as in fig. 1, 2, 7, and 8. The results obtained are shown in the following table:
example 6 accuracy of the detection method of the present invention
Accuracy is achieved by the recovery rate between the measured concentration and the theoretical concentration of the measured component and the total RSD of the recovery rate (n=9), which is required to be added to an accuracy solution with LOQ concentration, 100% limit concentration, 150% limit concentration, the recovery rate of N-bromosuccinimide should be between 70.0% and 130.0%, and the total RSD of the recovery rate (n=9) should be not more than 20.0%.
EXAMPLE 7 solution stability of the assay according to the invention
And (3) examining the rule of time variation of detection results after the control solution, the sample solution and the selective solution are placed for a period of time at room temperature, and providing a reference for the placement time of the control solution and the sample solution during detection.
The requirements are: compared with the reference solution of 0hr, the recovery rate of N-bromosuccinimide is 80.0% -120.0% in the room temperature investigation period, and no obvious change trend exists, so that the reference solution is stable in the room temperature investigation period;
if the N-bromosuccinimide is detected in the sample solution for 0hr, the sample solution is placed at room temperature for a period of time, the measured result change value is within 20% of the limit of the N-bromosuccinimide, and no obvious change trend exists, and the sample solution is stable during room temperature investigation; if the N-bromosuccinimide is not detected in the sample solution for 0hr, and the N-bromosuccinimide is still not detected in the sample solution after the sample solution is placed at room temperature for a period of time, the sample solution is stable during room temperature investigation;
the selective solution is placed at room temperature for a period of time, the recovery rate of the N-bromosuccinimide is 80.0-120.0%, and no obvious change trend exists, so that the selective solution is stable during room temperature investigation.
Claims (2)
1. The method for detecting the N-bromosuccinimide in the voriconazole is characterized by comprising the following steps of:
(1) Preparing solutions, namely preparing a blank solution, a reference stock solution, a reference solution, a sensitivity solution and a test solution respectively; the blank solution is a diluent 1 and a diluent 2; the control stock solution and the control solution comprise N-bromosuccinimide, a diluent 1 and a diluent 2; the sensitivity solution comprises N-bromosuccinimide, a diluent 1 and a diluent 2; the sample solution comprises voriconazole, a diluent 1 and a diluent 2; the diluent 1 is acetonitrile: the volume ratio V/V of the acetone is 1:1, and the diluent 2 is water;
(2) The measuring method comprises the following steps: respectively injecting a blank solution, a sensitivity solution, a reference substance solution and a test sample solution into a liquid chromatograph, recording a chromatogram, and performing chromatographic conditions as follows: chromatographic column: octadecylsilane chemically bonded silica is used as a filler; sample injection amount: 20 μl; column temperature: 30 ℃; flow rate: 0.4ml/min; the eluent is a mobile phase A-mobile phase B system; mobile phase a was a 10mM ammonium acetate solution containing 0.1% glacial acetic acid; the mobile phase B is: acetonitrile; the gradients of mobile phase a and mobile phase B are shown below:
the ion source parameters are as follows:
2. the method for testing N-bromosuccinimide in voriconazole according to claim 1, wherein the blank solution is prepared by the steps of: the blank solution is diluent 1 and diluent 2;
the preparation steps of the reference substance stock solution are as follows: taking an N-bromosuccinimide reference substance, precisely weighing, placing in a volumetric flask, adding a diluent 1 for dissolution, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a volumetric flask, adding the diluent 2 to dilute to a scale, and shaking to obtain a reference stock solution;
the preparation steps of the reference substance solution are as follows: precisely measuring the reference stock solution, placing in a volumetric flask, adding the diluent 1, diluting to scale, and shaking; precisely measuring the solution, placing in a volumetric flask, adding diluent 2, diluting to scale, and shaking to obtain reference solution;
the preparation steps of the sensitivity solution are as follows: precisely measuring the reference substance solution, placing in a volumetric flask, adding blank solution, diluting to scale, and shaking to obtain sensitivity solution;
the preparation steps of the sample solution are as follows: taking a sample, precisely weighing, placing in a volumetric flask, adding the diluent 1, performing ultrasonic dissolution, diluting to a scale, and shaking uniformly; precisely measuring the solution, placing in a volumetric flask, adding diluent 2, diluting to scale, shaking to precipitate sample, and filtering with a filter membrane to obtain sample solution;
the glacial acetic acid and ammonium acetate are above AR level;
acetonitrile, ultrapure water and acetone are HPLC grade;
the N-bromosuccinimide reference substance is purchased outsourced;
the chromatographic column is Thermo AcclaimTM 120C 18A 4.6X105 mm,5 mu m.
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