CN113295805A - Method for detecting hydrazine hydrate in medicine - Google Patents
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Abstract
The invention belongs to the technical field of medicine detection, and particularly discloses a method for detecting hydrazine hydrate in a medicine. The detection method provided by the invention has excellent linearity, detection limit, specificity and accuracy, and the method has good applicability and reliability and conforms to the regulations of medicine detection; moreover, the appropriate dosage and reaction conditions of the derivatization reagent are tested, so that the derivatization efficiency and the stability of the derivatization product are improved; parameters of liquid phase and mass spectrum conditions are determined, and the detection sensitivity of the derivative product and the resolution of an interference peak are improved.
Description
Technical Field
The invention belongs to the technical field of medicine detection, and particularly relates to a method for detecting hydrazine hydrate in a medicine.
Background
Hydrazine hydrate is used as a genotoxic impurity in medicines, and quantitative detection of the hydrazine hydrate is important for quality control of the medicines. Because hydrazine hydrate is unstable, direct detection is greatly influenced by interference factors, currently, a derivative liquid chromatography is mainly adopted for a detection method of hydrazine hydrate in a medicament, but the problems of long analysis time and poor sensitivity still exist. In order to solve the problem, patent CN108459107A discloses a method for determining hydrazine hydrate residue in a drug by using a liquid chromatography-mass spectrometry method. However, the accuracy and stability of this method still remain to be improved.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims at providing a method for detecting hydrazine hydrate in a medicament.
The purpose of the invention is realized by the following scheme:
a method for detecting hydrazine hydrate in a medicament comprises the following steps:
dissolving the drug with ethanol to obtain a test sample, adding a derivatization reagent into the test sample and a reference sample respectively, performing ultrasonic treatment at room temperature for 30-60 min, and performing derivatization reaction; detecting and analyzing by using a liquid chromatography-mass spectrometry system;
the derivatization reagent is p-dimethylaminobenzaldehyde solution;
the preparation method of the derivatization reagent comprises the following steps: dissolving p-dimethylaminobenzaldehyde with a glacial acetic acid-ethanol solution to a constant volume to obtain a p-dimethylaminobenzaldehyde solution, namely a derivative reagent;
the preparation method of the reference substance comprises the following steps: adding water to dilute the diamine standard solution to prepare hydrazine hydrate, and then carrying out gradient dilution to obtain a standard curve solution;
the volume ratio of the test sample or the reference sample to the p-dimethylaminobenzaldehyde solution is 1: (10-20).
Further, the concentration of the test sample is 1-10 mg/ml; the concentration of the p-dimethylaminobenzaldehyde solution is 10-30 mg/ml;
further, the volume ratio of the glacial acetic acid to the ethanol in the preparation method of the derivatization reagent is 1: 9;
further, the concentrations of the standard curve solutions are respectively 18.66 ng/ml, 37.31 ng/ml, 74.63 ng/ml, 186.56 ng/ml, 373.13ng/ml, 559.69 ng/ml, 746.25 ng/ml and 932.81 ng/ml.
Further, the liquid chromatography conditions were as follows:
mobile phase composition: a is formic acid-water (1: 1000), B is methanol;
gradient elution parameters are as in table 1:
TABLE 1
A chromatographic column: InfinityLab Poroshell 120 SB-AQ column (2.7 μm, 2.1X 100 mm);
flow rate: 0.27 ml/min-0.33 ml/min;
column temperature: 28-32 ℃;
sample introduction volume: 1 to 5. mu.l.
Further, the mass spectrum conditions are as follows:
an ion source: an ESI source;
polarity: a positive ion;
scanning mode: MRM;
a detector: triple quadrupole mass spectrometer
The scan parameters are as in table 2:
TABLE 2
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the detection method has excellent linearity, detection limit, specificity and accuracy, and the method has good applicability and reliability and conforms to the regulations of medicine detection;
2. the dosage and reaction conditions of the derivatization reagent are explored, and the derivatization efficiency and the stability of the derivatization product are improved;
3. the condition parameters of liquid phase and mass spectrum are determined, and the detection sensitivity of the derivative product and the resolution of interference peaks are improved.
Drawings
FIG. 1 shows the volume ratio of 1:9 standard graph.
FIG. 2 shows the volume ratio of 1:19 standard graph of the same.
FIG. 3 is a spectrum of the specificity of the spiked solution in example 5.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto. The medicine provided by the invention is a raw material medicine, a tablet or an injection. The room temperature of the invention is 20-32 ℃.
The reagents used in the examples are commercially available without specific reference.
Example 1
(1) Taking 0.5g of p-dimethylaminobenzaldehyde, precisely weighing, placing in a 25ml volumetric flask, adding a glacial acetic acid-ethanol (1: 9) solution for dissolving and fixing the volume to obtain a derivative reagent;
(2) putting a proper amount of hydrazine standard solution into a 10ml volumetric flask, adding water to dilute the hydrazine standard solution to a scale, shaking up the solution, and diluting the solution with ethanol to respectively prepare standard curve solutions with hydrazine hydrate concentration of 18.66-932.81 ng/ml (hydrazine hydrate limit percentage is 5-250%);
(3) dissolving 50mg of bulk drug powder (oseltamivir) in ethanol, diluting to constant volume with a 10mL volumetric flask to obtain a test solution, dissolving 50mg of bulk drug powder in a reference solution (373.13 ng/mL), and diluting to constant volume with a 10mL volumetric flask to obtain a standard solution;
(4) respectively taking an ethanol solvent, a standard curve solution, a test sample solution and a standard solution, adding a derivatization reagent for derivatization reaction, performing ultrasonic treatment at room temperature for 40min, and shaking up; wherein, the volume ratios of the ethanol solvent, the standard curve solution, the sample solution, the standard solution and the derivative reagent are respectively 1: 1. 1: 4. 1:9 and 1: 19;
(5) liquid chromatography conditions: a chromatographic column: InfinityLab Poroshell 120 SB-AQ column (2.7 μm, 2.1X 100 mm);
mobile phase: a: formic acid-water (1: 1000), B: methanol;
column temperature: 30 ℃;
sample introduction volume: 5 mu l of the solution;
collecting time: 10 min;
gradient program: as shown in table 3
TABLE 3
(6) Mass spectrum conditions: an ion source: an ESI source;
polarity: a positive ion;
scanning mode: MRM;
a detector: triple quadrupole mass spectrometer
The scan parameters are shown in table 4:
TABLE 4
(7) The calculation method comprises the following steps:
and (3) measuring the peak area of the standard curve solution, taking the hydrazine hydrate concentration c (ng/mL) as the abscissa and the peak area A as the ordinate, performing linear regression analysis by adopting a least square method, drawing a standard curve, and calculating a linear regression equation and a correlation coefficient. Calculating the content of hydrazine hydrate in the test sample according to a formula:
the formula is as follows:
y: peak area of the target compound in solution;
k: the slope of the standard curve;
b: a standard curve intercept;
c: the concentration of the target compound in the solution, ng/ml, was determined using the results calculated by the quantification workstation.
The formula is as follows:
the content is as follows: the content of the target compound in the test sample, ppm;
and (3) detecting the concentration: measuring the concentration of the target compound in the test solution, ng/ml, and calculating by adopting a quantitative workstation;
dilution volume: 10 ml;
weighing: the sample is weighed and measured in mg.
The test results show that the volume ratio is 1:1 or 1: at 4, the response of the derivatized product in the spiked solution was too high to exceed the maximum threshold of the instrument and was prone to residual effects. The volume ratio is 1: at 9, taking the standard curve solution as an example, as shown in FIG. 1, the linearity of the standard curve is poor, and the peak area and concentration are not proportional. When the volume ratio is 1:19, taking a standard curve solution as an example, as shown in FIG. 2, the correlation coefficient r of a linear regression equation is 0.998, which shows that the peak area of hydrazine hydrate has a good linear relation with the concentration in the concentration range of 37.31-932.81 ng/ml. Test results show that the derivatization conditions need to be strictly regulated and controlled to obtain a derivatization product with high purity, stability and good separation degree, wherein the detection requirement is met when the dosage of the derivatization reagent is controlled, namely the volume ratio of the sample solution to the derivatization reagent is 1: 19.
Example 2
Referring to the detection method of example 1, the volume ratio was 1:19, except that the temperature and time of the derivatization reaction were adjusted, the peak area of the 100% limit control solution (373.13 ng/mL) was measured, and the measurement was repeated 3 times to obtain an average value. The experimental parameters and results are shown in table 5 below.
The result shows that the derivatization can be completed at 25 ℃ for 40-60 min, and particularly, the derivatization efficiency is highest and the derivatization product is most stable at the time of ultrasonic treatment for 40 min. When the derivatization temperature is 50 ℃, the derivatization product in the system is unstable, the peak area greatly slides down, and an interference substance is possibly introduced to influence the determination result.
TABLE 5
Example 3
Referring to the assay method of example 1, the volume ratio was 1:19, except that the solvent of the derivatizing reagent was adjusted, the recovery rate of the spiked solution was measured, and the assay was repeated 6 times. The experimental parameters and results are shown in table 6 below.
The result shows that the solvent of the derivatization reagent adopts methanol to generate larger interference to the system, and the adopted aqueous solution can influence the solubility of the test sample, so that the method is not suitable for detecting hydrazine hydrate in the medicament. In a glacial acetic acid-ethanol (1: 9) system, the recovery rate of the added standard solution is highest in accuracy and strongest in stability, and the detection requirement is met.
TABLE 6
Example 4
Referring to the detection method of example 1, the volume ratio was 1:19, except that the mobile phase system was adjusted to detect the recovery rate of the spiked solution. The experimental parameters and results are shown in table 7 below.
The result shows that when the mobile phase adopts acetonitrile, the separation degree of the main drug and hydrazine hydrate is poor and the recovery rate error is large probably because of the over-strong elution capability. In the formic acid (0.1%) -methanol system, the best recovery results are obtained.
TABLE 7
Example 5
1. Specificity
The detection method of example 1 is adopted, the volume ratio is 1:19, the sample injection amount is adjusted to 1 mul, the ethanol solvent, the sample solution, the reference solution (with the concentration of 373.13 ng/ml) and the standard solution are respectively taken to be subjected to derivatization treatment by a derivatization reagent, the detection method is specific, the standard solution is taken as an example, and the figure is 3. The result shows that the retention time of hydrazine hydrate is 6.37min, and no miscellaneous peak appears, which indicates that the detection system of the application has no interference to detection and the method has good specificity.
2. Detection limit and quantification limit
The detection method of example 1 was adopted, the volume ratio was 1:19, the sample size was adjusted to 1. mu.l, the detection limit: a control solution (18.66 ng/ml) was injected continuously for 3 times.
And (4) quantitative limit: a control solution (37.31 ng/ml) was injected continuously for 6 times.
The detection limit concentration was 18.66 ng/ml (3.73 ppm), corresponding to 5% detectable of the limit concentration, where the average S/N was 534.0. The quantitative limit concentration is 37.31 ng/ml (74.61 ppm), 10% of the quantitative limit concentration can be quantitatively detected, and the peak area RSD of hydrazine hydrate in 6 continuous quantitative limit solutions is 1.4%.
3. Accuracy of
The detection method of example 1 is adopted, the volume ratio is 1:19, the sample injection amount is adjusted to 1 mul, 50mg of test sample is respectively added into control solution with the concentration of 186.56, 373.13 and 559.69 ng/ml in sequence to prepare standard solutions which are equivalent to 50 percent, 100 percent and 150 percent of the limit concentration of hydrazine hydrate, each concentration is prepared for 3 times, sample injection is respectively carried out, a chromatogram is recorded, and the recovery rate result is calculated.
The formula is as follows:
Cmeasurement of: recovering the measured concentration of the target compound in the solution, ng/ml;
Csample (I): test solutionConcentration of a sample of the compound of interest in the liquid, ng/ml;
Cmark adding device: the concentration of the target compound theoretically added in the solution, ng/ml, was recovered.
The results are shown in Table 8. The recovery rate of hydrazine hydrate is in the range of 84.0-103.3%, the RSD is 5.7%, and the method has high accuracy.
TABLE 8
4. Stability of
The test method of example 1 was used, the volume ratio was 1:19, the amount of sample was adjusted to 1. mu.l, the sample solution was left at 25 ℃ for 29 hours in the dark, and the stability of the test solution, the 100% limiting concentration control solution and the 100% limiting concentration spiked test solution was examined, and the test results are shown in Table 9.
The result shows that the measured concentration of hydrazine hydrate accounts for 97.9-101.1% of the initial (0 h) measured concentration, the requirement is met, and the 100% limit concentration control solution is stable within at least 29 h.
TABLE 9
5. Durability
Referring to the detection method of example 1, the volume ratio is 1:19, the sample amount is adjusted to 1 μ l, a standard curve is drawn by using a standard curve solution under experimental conditions, and then a standard sample solution with 100% limit concentration is added for detection and analysis, and the difference is only that the liquid chromatography analysis parameters are adjusted: flow rate and column temperature. The experimental parameters and results are shown in table 10 below. The result shows that under the conditions that the column temperature fluctuates within the range of 28-32 ℃, the flow rate fluctuates within the range of 0.27-0.33 ml/min, blank solutions are not interfered for detection, the RSD value of the peak area of hydrazine hydrate in the 6-pin system applicability solution is 1.1-2.4%, the hydrazine hydrate recovery rate is 102.1-107.7%, and the method has good durability.
Watch 10
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. A method for detecting hydrazine hydrate in a medicament is characterized by comprising the following steps:
dissolving the drug with ethanol to obtain a test sample, adding a derivatization reagent into the test sample and a reference sample respectively, performing ultrasonic treatment at room temperature for 30-60 min, and performing derivatization reaction; detecting and analyzing by using a liquid chromatography-mass spectrometry system;
the derivatization reagent is p-dimethylaminobenzaldehyde solution;
the preparation method of the derivatization reagent comprises the following steps: dissolving p-dimethylaminobenzaldehyde with a glacial acetic acid-ethanol solution to a constant volume to obtain a p-dimethylaminobenzaldehyde solution, namely a derivative reagent;
the preparation method of the reference substance comprises the following steps: adding water to dilute the diamine standard solution to prepare hydrazine hydrate, and then carrying out gradient dilution to obtain a standard curve solution;
the volume ratio of the test sample or the reference sample to the p-dimethylaminobenzaldehyde solution is 1: (10-20).
2. The method of claim 1, wherein: the concentration of the p-dimethylaminobenzaldehyde solution is 10-30 mg/ml.
3. The method of claim 1, wherein: the concentration of the test sample is 1-10 mg/ml.
4. The method of claim 1, wherein: the volume ratio of the glacial acetic acid to the ethanol in the preparation method of the derivatization reagent is 1: 9.
5. The method of claim 1, wherein: the concentrations of the standard curve solutions were 18.66 ng/ml, 37.31 ng/ml, 74.63 ng/ml, 186.56 ng/ml, 373.13ng/ml, 559.69 ng/ml, 746.25 ng/ml and 932.81 ng/ml, respectively.
6. The method of claim 1, wherein the liquid chromatography conditions are as follows:
mobile phase composition: a is formic acid-water with the volume ratio of 1: 1000, B is methanol;
gradient elution parameters are as in table 1:
TABLE 1
A chromatographic column: InfinityLab Poroshell 120 SB-AQ column;
flow rate: 0.27 ml/min-0.33 ml/min;
column temperature: 28-32 ℃;
sample introduction volume: 1 to 5. mu.l.
7. The method of claim 1, wherein the mass spectrometry conditions are:
an ion source: an ESI source;
polarity: a positive ion;
scanning mode: MRM;
a detector: a triple quadrupole mass spectrometer detector;
the scan parameters are as in table 2:
TABLE 2
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| CN115266980A (en) * | 2022-07-28 | 2022-11-01 | 海南通用三洋药业有限公司 | Method for detecting hydrazine hydrate impurity in tazobactam sodium |
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| CN115266980A (en) * | 2022-07-28 | 2022-11-01 | 海南通用三洋药业有限公司 | Method for detecting hydrazine hydrate impurity in tazobactam sodium |
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