CN113671085B - Method for detecting 2-azido-3-methylbutyric acid in valsartan - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting 2-azido-3-methylbutyric acid in valsartan, which is a convenient, efficient and accurate detection method for solving the problem of detecting 2-azido-3-methylbutyric acid in valsartan, and can detect the content of 2-azido-3-methylbutyric acid in valsartan, thereby effectively ensuring the medication safety and facilitating the quality control of valsartan bulk drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting 2-azido-3-methylbutyric acid in valsartan.
Background
Valsartan (valsartan) is chemically named as (S) -N-pentanoyl-N- [4- (2-tetrazolyl) phenyl ] benzyl valine, is an angiotensin II (angiotensin II) AT1 receptor antagonist, is a novel antihypertensive drug after a calcium channel blocker and an Angiotensin Converting Enzyme Inhibitor (ACEI), has small side effect, unique action mechanism, good tolerance, convenient taking and obvious curative effect, simultaneously has the effect of protecting target organs such as heart, brain, kidney and the like, and has very wide application prospect.
2-azido-3-methylbutyric acid, CAS No.:81439-78-3, structural formula:
the valsartan is a process impurity in the synthesis process of the valsartan, and the impurity needs to be controlled due to the fact that the valsartan has a genotoxicity warning structure of an azide group.
Genotoxic impurities are impurities which can react with DNA to cause DNA damage, can induce gene mutation at a very low level and can cause cancer, and have strong toxicity to the safety of medication, in recent years, more and more cases occur because trace genotoxic impurity residues are found in marketed drugs to generate a large-scale medical accident and are forcibly recalled by FDA, and a great economic loss is caused by a dosing factory, in recent years, national regulatory agencies such as ICH, FDA, EMA and the like have more definite requirements on genotoxic impurities, more and more pharmaceutical enterprises pay attention to the control box detection of the genotoxic impurities in the research and development process of new drugs, and the guiding principles related to genotoxic and carcinogenic impurities are issued, wherein the toxicological attention threshold (TTC) value of the genotoxic impurities in M7 is 1.5 mu g/day, while the maximum daily dose of valsartan in a valsartan tablet is 320 mg/day, and the finished product of valsartan-methyl butyrate-4 ppm is calculated according to the formula = TTC/maximum daily dose.
At present, no document discloses a method for detecting the content of 2-azido-3-methylbutyric acid in valsartan, the invention discloses a method for detecting 2-azido-3-methylbutyric acid in valsartan for the first time, and provides a convenient, efficient and accurate detection method for solving the problem of detecting 2-azido-3-methylbutyric acid in valsartan, and the method can detect the content of 2-azido-3-methylbutyric acid in valsartan, thereby effectively ensuring the medication safety and facilitating the quality control of bulk drugs of valsartan.
Disclosure of Invention
The invention provides a method for detecting 2-azido-3-methylbutyric acid in valsartan, which is convenient, efficient and accurate to solve the detection problem of valsartan, can detect the content of 2-azido-3-methylbutyric acid in valsartan, thereby effectively ensuring the medication safety and facilitating the quality control of valsartan, is convenient, efficient and accurate, completely accords with the guiding principle of Chinese pharmacopoeia method verification in the aspects of system applicability, repeatability, specificity and accuracy, and can be used for the quality control of valsartan bulk drugs.
In order to achieve the purpose, the invention provides the following technical scheme:
a method for detecting 2-azido-3-methylbutyric acid in valsartan, which comprises the following steps: (1) Preparing solution, namely preparing blank solution, sensitivity solution, reference solution and test solution respectively.
(2) The measuring method comprises the following steps: determining the content of 2-azido-3-methylbutyric acid in the valsartan by adopting LC-MS, respectively feeding a blank solution, a sensitivity solution, a reference solution and a test solution after the system is stabilized, and recording a chromatogram;
the chromatographic conditions are as follows: taking octadecylsilane chemically bonded silica as a chromatographic column of a filler, wherein the sample injection amount is as follows: 5 μ l, column temperature: 30 ℃, flow rate: 0.4ml/min, mobile phase with formic acid: the water system is a mobile phase A, acetonitrile is used as a mobile phase B, and gradient elution is adopted;
the MS conditions were as follows: temperature of the drying gas: 320 ℃, flow rate of drying gas: 8L/min, atomizing gas pressure: 40 psi, sheath gas temperature: 350 ℃, sheath gas flow rate: 10 L/min, capillary voltage: 3500V, polarity: negative pole, scan mode: SIM, acquisition time: 4.0min-8.0min, EMV:0V, SIM Ion (m/z): 142.0, fragment: 66V, dwell:100ms, acceleration voltage: 5V.
Further, the blank solution is acetonitrile: water =50 (V/V), the mobile phase being:
a mobile phase A: formic acid: water =1 (v/v), mobile phase B: acetonitrile, the control solution: taking a proper amount of 2-azido-3-methylbutyric acid, placing the 2-azido-3-methylbutyric acid in a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the blank liquid to a scale, and shaking up; the sensitivity solution: taking a proper amount of reference substance solution, placing the reference substance solution in a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the reference substance solution to a scale, and shaking up; the test solution is as follows: taking a proper amount of test sample, placing the test sample in a volumetric flask, adding a blank solution, ultrasonically dissolving, diluting to a scale, shaking up, and using a chromatographic column of ThermoAcclaim TM RSLC 120 C18.1 × 100mm,2.2 μm or a column of comparable performance.
Further, the mobile phase gradient process is as follows:
further, the measurement method of the present invention comprises the steps of:
(1) Preparing a solution:
acetonitrile: HPLC; formic acid: HPLC; water: ultrapure water; 2-azido-3-methylbutyric acid: self-made or purchased;
blank solution: acetonitrile: water =50 (V/V);
control stock (1): precisely weighing about 23.5mg of 2-azido-3-methylbutyric acid reference substance, placing the reference substance into a 50ml measuring flask, adding a diluent to dissolve and dilute the reference substance to a scale, and shaking up; precisely measuring 1.0ml of the solution, placing the solution into a 25ml measuring flask, adding the diluent to dilute to the scale, and shaking up. (concentration: 18.8. Mu.g/ml)
Control stock (2): precisely measure the control stock solution (1) 1.0ml, place in a 20ml measuring flask, add the diluent to dilute to the scale, and shake up. (concentration: 940 ng/ml)
Control solution: the control stock solution (500. Mu.l of 2) was measured out precisely and placed in a 10ml measuring flask, diluted to the mark with diluent and shaken up. (concentration: 47 ng/ml)
Sensitivity solution: precisely measuring 1.0ml of the reference solution, placing the reference solution in a 10ml measuring flask, adding the blank solution to dilute to the scale, and shaking up. (concentration: 4.7 ng/ml)
Test solution: taking about 100mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding an appropriate amount of diluent, dissolving by ultrasonic, adding the diluent to dilute to a scale, and shaking up. (concentration: valsartan 10 mg/ml)
Chromatographic conditions are as follows:
the instrument comprises: agilent InfinityII 1290 UHPLC + Agilent 6470 ESI (-) -QQQ-MS, electronic analytical balance;
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler (e.g., thermoAcclaim RSLC 120 C18.1 × 100mm,2.2 μm or equivalent performance chromatographic column)
Sample introduction amount: 5 mu l; column temperature: 30 ℃; flow rate: 0.4ml/min; mobile phase A: formic acid: water =1 (v/v); and (3) mobile phase B: acetonitrile;
(1) The determination method comprises the following steps:
after the system is stabilized, a blank solution 1 needle, a sensitivity solution 1 needle, a reference substance solution 6 needle, a blank solution 1 needle and a test solution 1 needle are added, and a spectrogram is recorded.
Result (ppm) = (R) U /R S )×(C S /C U )
Wherein: r is U : 2-azido in test solution atlas-peak area of 3-methylbutyric acid;
R S : 6-average peak area of 2-azido-3-methylbutyric acid in the chromatogram of the control solution;
C S : concentration of 2-azido-3-methylbutyric acid (ng/ml) in the control solution;
C U : concentration of test solution (mg/ml).
Limitation:
the method for detecting the 2-azido-3-methylbutyric acid in the valsartan further comprises method verification before detection, wherein the method verification is that according to the chromatographic conditions of formal detection, the measurement result is as follows:
the invention discloses a method for detecting 2-azido-3-methylbutyric acid in valsartan for the first time, provides a convenient, efficient and accurate detection method for solving the problem of detecting 2-azido-3-methylbutyric acid in valsartan, and can detect the content of 2-azido-3-methylbutyric acid in valsartan, thereby effectively ensuring the medication safety.
Drawings
FIG. 1 is a blank solution spectrum of 2-azido-3-methylbutyric acid in valsartan
FIG. 2 is a spectrum of a 2-azido-3-methylbutyric acid control solution in valsartan
FIG. 3 is a spectrum of a test solution of 2-azido-3-methylbutyric acid in valsartan
FIG. 4 is a graph of a 2-azido-3-methylbutyric acid sensitive solution profile in valsartan
FIG. 5 is a graph of a 2-azido-3-methylbutyric acid selective solution in valsartan
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1:
(1) Preparing a solution:
acetonitrile: HPLC; formic acid: HPLC; water: ultrapure water; 2-azido-3-methylbutyric acid: self-made or purchased;
blank solution: acetonitrile: water =50 (V/V);
control stock (1): precisely weighing about 23.5mg of 2-azido-3-methylbutyric acid reference substance, placing the reference substance into a 50ml measuring flask, adding a diluent to dissolve and dilute the reference substance to a scale, and shaking up; precisely measuring 1.0ml of the solution, placing the solution into a 25ml measuring flask, adding the diluent to dilute to the scale, and shaking up. (concentration: 18.8. Mu.g/ml)
Control stock (2): precisely measure the control stock solution (1); 1.0ml, place in a 20ml measuring flask, add diluent to dilute to the scale, shake well. (concentration: 940 ng/ml)
Control solution: the control stock solution (500. Mu.l of 2) was measured out precisely and placed in a 10ml measuring flask, diluted to the mark with diluent and shaken up. (concentration: 47 ng/ml)
Sensitivity solution: precisely measuring 1.0ml of the reference solution, placing the reference solution in a 10ml measuring flask, adding the blank solution to dilute to the scale, and shaking up. (concentration: 4.7 ng/ml)
Test solution: taking about 100mg of a test sample, precisely weighing, placing in a 10ml measuring flask, adding an appropriate amount of diluent, dissolving by ultrasonic, adding the diluent to dilute to a scale, and shaking up. (concentration: valsartan 10 mg/ml)
Selective solution: taking about 100mg of the sample, accurately weighing, placing in a 10ml measuring flask, accurately weighing 500 μ l of reference substance stock solution (2), placing in the measuring flask, adding appropriate amount of diluent, dissolving by ultrasonic, adding diluent to dilute to scale, and shaking. ( Concentration: valsartan 10mg/ml and 2-azido-3-methylbutyric acid 47ng/ml )
Test solution (spiked): taking about 100mg of the sample, accurately weighing, placing in a 10ml measuring flask, accurately weighing 500 μ l of reference substance stock solution (2), placing in the measuring flask, adding appropriate amount of diluent, dissolving by ultrasonic, adding diluent to dilute to scale, and shaking. (the concentration: valsartan 10mg/ml, 2-azido-3-methylbutyric acid 47 ng/ml) and 6 parts of the solution are prepared by the same method;
LOQ solution: according to the S/N value of the 2-azido-3-methylbutyric acid obtained by the sensitivity solution, the dilution ratio is adjusted to the S/N value of the 2-azido-3-methylbutyric acid not less than 10. 6 portions of the mixture are prepared by the same method.
LOD solution: precisely measuring 2.0ml of LOQ solution, placing in a 10ml measuring flask, adding blank solution to dilute to scale, and shaking up;
linear solution-50%: the control stock solution (2) was measured accurately (250. Mu.l in 10ml measuring flask), diluted to the mark with diluent and shaken well. (concentration: 23.5 ng/ml)
Linear solution-80%: the control stock solution (400. Mu.l of 2) was measured out precisely and placed in a 10ml measuring flask, diluted to the mark with diluent and shaken up. (concentration: 37.6 ng/ml)
Linear solution-100%: precisely measure the control stock solution (2) 500. Mu.l into a 10ml measuring flask, add the diluent to the scale, and shake up. (concentration: 47 ng/ml)
Linear solution-120%: precisely measure the control stock solution (2) in 600. Mu.l, put it in a 10ml measuring flask, add the diluent to the scale, and shake it up. (concentration: 56.4 ng/ml)
Linear solution-150%: the control stock solution (750. Mu.l of 2) was measured accurately and placed in a 10ml measuring flask, diluted to the mark with diluent and shaken well. (concentration: 70.5 ng/ml)
Accuracy solution-100%: precisely weighing about 100mg of a test sample, placing the test sample in a 10ml measuring flask, precisely weighing 500 mu l of accurate stock solution, placing the accurate stock solution in the measuring flask, adding a proper amount of diluent, dissolving by ultrasonic waves, adding the diluent to dilute to a scale, and shaking up. (concentration: valsartan 10mg/ml, 2-azido-3-methylbutyric acid 47 ng/ml) 3 parts were prepared in the same manner.
Accuracy solution-150%: precisely weighing about 100mg of a test sample, placing the test sample in a 10ml measuring flask, precisely weighing 750 mu l of accurate stock solution, placing the accurate stock solution in the measuring flask, adding a proper amount of diluent, dissolving by ultrasonic waves, adding the diluent to dilute to a scale, and shaking up. (the concentration: valsartan 10mg/ml, 2-azido-3-methylbutyric acid 70.5 ng/ml) 3 parts were prepared in the same manner.
Chromatographic conditions are as follows:
the instrument comprises the following steps: agilent InfinityII 1290 UHPLC + Agilent 6470 ESI (-) -QQQ-MS and electronic analytical balance;
a chromatographic column: chromatographic column using octadecylsilane chemically bonded silica as filler (e.g., thermoAcclaim RSLC 120 C18.1 × 100mm,2.2 μm or equivalent performance chromatographic column)
Sample introduction amount: 5 mu l; column temperature: 30 ℃; flow rate: 0.4ml/min; a mobile phase A: formic acid: water =1 (v/v); and (3) mobile phase B: acetonitrile;
(1) The determination method comprises the following steps:
after the system is stabilized, a blank solution 1 needle, a sensitivity solution 1 needle, a reference substance solution 6 needle, a blank solution 1 needle and a test solution 1 needle are added, and a spectrogram is recorded.
Result (ppm) = (R) U /R S )×(C S /C U )
Wherein: r U : peak area of 2-azido-3-methylbutyric acid in the test solution map;
R S :6, the average peak area of 2-azido-3-methylbutyric acid in the chromatogram of the reference solution;
C S : concentration of 2-azido-3-methylbutyric acid (ng/ml) in the control solution;
C U : concentration of test solution (mg/ml).
Limitation:
example 2: system applicability
The system applicability is realized by measuring the S/N value of 2-azido-3-methylbutyric acid in the sensitivity solution and the RSD of the peak area of 2-azido-3-methylbutyric acid in 6-needle reference substance solution, and the S/N of 2-azido-3-methylbutyric acid in the sensitivity solution is required to be more than or equal to 10; RSD in the peak area of 2-azido-3-methylbutyric acid in 6-needle control solutions should not be more than 10.0%. In order to confirm the system applicability during the sequence running process, 1 needle of reference solution is fed every about 8 hours and at the end of the sequence during the verification process, and the RSD (measured by the peak area of 2-azido-3-methylbutyric acid) in 6 successive needles of reference solution is required to be not more than 10.0 percent.
Example 3: specificity
The specificity is realized by measuring the separation degree between the 2-azido-3-methylbutyric acid peak and the adjacent peak in the selective solution without interfering the detection of the blank solution, and the separation degree between the 2-azido-3-methylbutyric acid peak and the adjacent peak in the selective solution is not less than 1.5.
Example 4: precision degree
Repeatability: the repeatability is realized by measuring the RSD of the measurement result of the 2-azido-3-methylbutyric acid in 6 parts of test solution (added standard), and the RSD of the measurement result of the 2-azido-3-methylbutyric acid in 6 parts of test solution (added standard) is required to be not more than 10.0%.
Example 5: detection limit and quantification limit
The detection limit is determined by detecting that the ratio of the response signal to the noise is not less than 3:1 is obtained; the limit of quantitation is determined by detecting that its response signal to noise ratio is not less than 10:1, and (b). Under the quantitative limit concentration level, 6 parts of quantitative limit solution are repeatedly inspected, the RSD of the unit concentration peak area of 2-azido-3-methylbutyric acid in 6 parts of LOQ solution is required to be not more than 20.0 percent, the LOQ 2-azido-3-methylbutyric acid is required to be not more than 1.41ppm, and the S/N is not less than 10; the S/N of the 2-azido-3-methylbutyric acid in the LOD solution is not less than 3, and the LOD is less than LOQ.
Example 6: linearity and range
And uniformly taking 6 points in the limit concentration range of LOQ concentration-150%, and drawing a curve by taking the concentration as an abscissa and the peak area as an ordinate. It is required that 2-azido-3-methylbutyric acid should be linear within the range of LOQ concentration to the 150% limit concentration, the square of the correlation coefficient R (R2) should not be less than 0.99, and the absolute value of the y-axis intercept should be within 25% of the 100% concentration response value.
Example 7: accuracy of
Accuracy is achieved by recovery between measured and theoretical concentrations of the measured component and total RSD of recovery (n = 9). It is required that the recovery rate of 2-azido-3-methylbutyric acid should be between 70.0% and 130.0% and the total RSD of recovery (n = 9) should not be greater than 20.0% in an accuracy solution with LOQ concentration, 100% limit concentration, 150% limit concentration added.
Example 8: durability
And (3) observing the rule that the reference substance solution, the test solution and the selective solution are placed at room temperature for a period of time and then are injected, and detecting the change of the detection result along with the time, so as to provide reference for the placing time of the reference substance solution and the test solution during detection.
The method comprises the following steps: compared with the reference solution for 0hr, the recovery rate of the 2-azido-3-methylbutyric acid is between 80.0 and 120.0 percent within a period of time of the reference solution being placed at room temperature, and no obvious change trend exists, so that the reference solution is stable during the investigation at room temperature;
if the test solution detects 2-azido-3-methylbutyric acid within 0hr, the test solution is placed at room temperature for a period of time, the change value of the measurement result is within 20% of the limit, and no obvious change trend exists, so that the test solution is stable during the investigation at room temperature; if the test solution does not detect the 2-azido-3-methylbutyric acid within 0hr, and if the test solution is placed at room temperature for a period of time, no 2-azido-3-methylbutyric acid is detected, the test solution is stable during the examination at room temperature;
the recovery rate of the 2-azido-3-methylbutyric acid should be between 80.0% and 120.0% within a period of time of the selective solution being placed at room temperature, and no obvious change trend exists, so that the selective solution is stable during the room temperature examination.
Claims (2)
1. A method for detecting 2-azido-3-methylbutyric acid in valsartan, characterized by comprising the following steps:
(1) Preparing solutions, namely preparing a blank solution, a sensitivity solution, a reference solution and a test solution respectively;
(2) The determination method comprises the following steps: determining the content of 2-azido-3-methylbutyric acid in the valsartan by adopting LC-MS, respectively feeding a blank solution, a sensitivity solution, a reference solution and a test solution after the system is stabilized, and recording a chromatogram;
the chromatographic conditions are as follows: thermo Acclaim RSLC 120 C18.1 × 100mm,2.2 μm, sample size: 5 μ l, column temperature: 30 ℃, flow rate: 0.4ml/min, mobile phase with formic acid: the water system is a mobile phase A, acetonitrile is used as a mobile phase B, and the mobile phase is as follows: a mobile phase A: formic acid: water volume ratio =1: acetonitrile, and gradient elution, wherein the mobile phase gradient process is as follows:
the MS conditions were as follows: temperature of the drying gas: 320 ℃, flow rate of drying gas: 8L/min, atomizing gas pressure: 40 psi, sheath gas temperature: 350 ℃, sheath gas flow rate: 10 L/min, capillary voltage: 3500V, polarity: negative pole, scan mode: SIM, acquisition time: 4.0min-8.0min, EMV:0V, SIM Ion (m/z): 142.0, fragment: 66V, dwell:100ms, acceleration voltage: 5V.
2. The method of claim 1, wherein:
the blank solution is acetonitrile: water volume ratio = 50;
the control solution: taking a proper amount of 2-azido-3-methylbutyric acid, placing the 2-azido-3-methylbutyric acid in a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the blank liquid to a scale, and shaking up;
the sensitivity solution: taking a proper amount of reference substance solution, placing the reference substance solution in a volumetric flask, adding a proper amount of blank liquid to dissolve and dilute the reference substance solution to a scale, and shaking up;
the test solution is as follows: taking a proper amount of a test article, placing the test article in a volumetric flask, adding a blank solution, ultrasonically dissolving, diluting to a scale, and shaking up.
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