CN114414675B - Method for detecting toxic impurities of halogenated alkane genes in pentoxifylline intermediate - Google Patents
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Abstract
The invention relates to the field of analytical chemistry, in particular to a method for detecting toxic impurities of halogenated alkane genes in a pentoxifylline intermediate. The detection method for the potentially halogenated alkane genotoxic impurities 3-chloropropene, 3-bromopropylene and 1-bromopropane in the 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran pentoxifylline intermediate synthesized by using the 1, 3-bromochloropropane as the starting material has the advantages of high detection sensitivity, low detection limit, short detection time, obvious improvement on the detection working efficiency, accurate and reliable detection result, good linear relation, good precision and durability, capability of monitoring the quality stability of the pentoxifylline intermediate and further guarantee and basis for the clinical medication safety of the pentoxifylline.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a method for detecting toxic impurities of halogenated alkane genes in a pentoxifylline intermediate.
Background
The pentoxifylline is a dimethyl xanthine derivative, and can reduce blood viscosity, improve blood fluidity, promote microcirculation of ischemic tissues, and increase oxygen supply of special organs. Pentoxifylline can improve erythrocyte deformability by inhibiting phosphodiesterase and increasing adenosine triphosphate in cells, and can also reduce fibrinogen and inhibit erythrocyte and platelet aggregation. It is mainly suitable for treating cerebral blood circulation disorder such as transient ischemic attack, apoplexy sequela, and cerebral dysfunction caused by cerebral ischemia, protecting cardiovascular and cerebrovascular vessels, improving heart function of patients with chronic heart failure and idiopathic dilated cardiomyopathy, and treating peripheral blood circulation disorder diseases such as thromboangiitis obliterans.
5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran is a pentoxifylline intermediate substance, 1, 3-bromochloropropane is a starting material for synthesizing 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran, and 3-chloropropene, 3-bromopropylene and 1-bromopropane are impurity substances of 1, 3-bromochloropropane, and the three compounds all contain genotoxicity warning structures. Acceptable limits for 3-chloropropene, 3-bromopropene, 1-bromopropane = TTC (μ g/day) × 1000/MDD (mg/day) =1.5 μ g/day × 1000/1200 mg/day =1.25ppm (ng/mg) according to ICH M7 guidelines, where TTC denotes toxicological thresholds and MDD denotes maximum daily dose.
The sensitivity of the conventional gas chromatography detection method cannot meet the detection requirements of the haloalkane genotoxic impurities (3-chloropropene, 3-bromopropylene and 1-bromopropane) in the pentoxifylline intermediate, and the technical difficulty exists in establishing a detection method capable of accurately and reliably detecting 3-chloropropene, 3-bromopropylene and 1-bromopropane. At present, no detection method capable of meeting the requirement is found.
Disclosure of Invention
Aiming at the fact that no detection method for the genotoxic impurities of the haloalkanes in the pentoxifylline intermediate exists at present, the invention provides the detection method for the genotoxic impurities of the haloalkanes in the pentoxifylline intermediate, which can monitor the quality stability of the 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran in the pentoxifylline intermediate, thereby providing guarantee for the safety of clinical medication of the pentoxifylline.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
the method for detecting the halogenated alkane genotoxic impurities in the pentoxifylline intermediate specifically comprises the following steps: preparing a solution to be detected by using an organic solvent, and detecting the toxic impurities of the halogenated alkane gene of the pentoxifylline intermediate by using a gas chromatography-mass spectrometry combined method; the pentoxifylline intermediate is 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran, and the haloalkane genotoxic impurities comprise 3-chloropropene, 3-bromopropylene and 1-bromopropane;
the chromatographic conditions of the gas chromatography include: the temperature program of the gas chromatograph is as follows: the initial temperature is 37 to 43 ℃, the temperature is maintained for 3min, the temperature is increased to 127 to 133 ℃ at the speed of 9.5 to 10.5 ℃/min, and then the temperature is increased to 177 to 183 ℃ at the speed of 24.5 to 25.5 ℃/min;
the conditions of the mass spectrum include: detecting by using a triple quadrupole tandem mass spectrometer, wherein the temperature of a quadrupole is 150 ℃; adopting an EI ion source, wherein the temperature of the ion source is 200-300 ℃.
Preferably, the organic solvent is one of methanol, dichloromethane or chloroform, more preferably methanol.
The method for detecting the toxic impurity of the halogenated alkane gene in the pentoxifylline intermediate provided by the invention has the following advantages:
for the detection of potential halogenated alkane genotoxic impurities 3-chloropropene, 3-bromopropylene and 1-bromopropane in 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran synthesized pentoxifylline intermediate by taking 1, 3-bromochloropropane as a starting material, the gas chromatography-mass spectrometry combined detection method provided by the invention has the advantages of high detection sensitivity, low detection limit, short detection time, obvious improvement on the detection working efficiency, accurate and reliable detection result, good linear relation, good precision and durability, capability of monitoring the quality stability of the pentoxifylline intermediate and further providing guarantee and basis for the clinical medication safety of pentoxifylline.
Preferably, the solution to be detected comprises a reference solution, and the concentrations of the 3-chloropropene, the 3-bromopropylene and the 1-bromopropane in the reference solution are 25.00-200.00ng/ml.
Preferably, the chromatographic conditions of the gas chromatograph further comprise: the running temperature is 280 ℃, and the running temperature is maintained for 7 to 9min; the temperature of a sample inlet is 220 ℃; the transmission line temperature is 280 ℃;
preferably, the chromatographic conditions of the gas chromatograph further comprise: the sample introduction mode is divided sample introduction, and the division ratio is 10:1.
preferably, the chromatographic conditions of the gas chromatograph further comprise: the length of the capillary chromatographic column is 15 to 75m, the inner diameter is 0.15 to 0.53mm, and the thickness of the stationary phase coating liquid film is 0.84 to 3.0 mu m.
More preferably, the chromatographic conditions of the gas chromatograph further comprise: the capillary chromatographic column has a column length of 60m, an inner diameter of 0.25mm, and a stationary phase coating liquid film thickness of 1.4 μm.
Preferably, the fixing solution of the capillary chromatographic column is 6wt% cyanopropylphenyl-94 wt% polydimethylsiloxane.
Preferably, the capillary chromatography column is of the type Agilent VF-624ms.
Preferably, the chromatographic conditions of the gas chromatograph further comprise: helium is used as a carrier gas, and the flow rate of the carrier gas is 0.9 to 1.1mL/min.
Preferably, the chromatographic conditions of the gas chromatograph further comprise: the temperature of a sample inlet is 217 to 223 ℃; the sample injection amount is 0.9 to 1.1 mu L.
Preferably, the mass spectrometry conditions further comprise: the ion detection mode is a multi-reaction detection mode.
Preferably, the mass spectrometry conditions further comprise:
the quantitative ion of the 3-chloropropene is more than 76, the collision energy of the quantitative ion is more than 6 eV, the collision energy of the qualitative ion is more than 41, and the collision energy of the qualitative ion is 12 eV;
the quantitative ion of the 3-bromopropylene is more than 120 & gt 41, the collision energy of the quantitative ion is 4 eV, the qualitative ion is more than 41, and the collision energy of the qualitative ion is 12 eV;
the quantitative ion of 1-bromopropane is 124 & gt 43, the quantitative ion collision energy is 2 eV, the qualitative ion collision energy is 43 & gt 39, and the qualitative ion collision energy is 6 eV.
Preferably, the mass spectrometry conditions further comprise: the ionization energy was 70eV.
Drawings
FIG. 1 is a chromatogram of a blank solvent (methanol) provided in example 1;
FIG. 2 is a chromatogram of a control solution provided in example 1;
FIG. 3 is a chromatogram of the test solution provided in example 1;
fig. 4 is a chromatogram of a mixed solution of a test sample and a control sample provided in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
the method for detecting the toxic impurity of the halogenated alkane gene in the pentoxifylline intermediate specifically comprises the following steps:
1.1 solution preparation
Precisely weighing 1g of a test sample, placing the test sample in a 10mL volumetric flask, adding methanol to dissolve the test sample and diluting the test sample to a scale, and preparing a solution containing 10mg of the test sample in each 1mL of the solution as a test sample solution;
precisely dissolving 3-chloropropene, 3-bromopropylene and 1-bromopropane respectively in appropriate amount, diluting with methanol, and mixing to obtain mixed solution containing 3-chloropropene 5000.00ng, 3-bromopropylene 5000.00ng and 1-bromopropane 5000.00ng per 1ml as reference stock solution;
taking a proper amount of reference stock solution, diluting with methanol to prepare a mixed solution containing 125.00ng of 3-chloropropene, 125.00ng of 3-bromopropylene and 125.00ng of 1-bromopropane in every 1mL as a reference solution;
precisely weighing 1g of the test sample, placing the test sample in a 10mL volumetric flask, adding 0.25mL of the reference sample stock solution, adding methanol for dissolving, and diluting to scale to obtain a mixed solution of the test sample and the reference sample.
1.2 Method for detecting genotoxic impurities in halogenated alkanes of pentoxifylline intermediate
Detecting the solution by using a gas chromatography-mass spectrometry combined method, wherein the chromatographic conditions are as follows: the type of the chromatographic column: agilent VF-624ms; specification of chromatographic column: 60m 0.25mm 1.4 μm; sample inlet temperature: 220 ℃; carrier gas: helium (99.999% purity), flow rate of 1 mL/min; the split ratio is as follows: 10, a step of; sample introduction volume: 1 mu L of the solution; temperature rising procedure: the initial temperature is 40 ℃, the temperature is maintained for 3min, the temperature is increased to 130 ℃ at the speed of 10 ℃/min, and then the temperature is increased to 180 ℃ at the speed of 25 ℃/min; the operation temperature is 280 ℃, and the operation time is maintained for 8min; the temperature of a sample inlet is 220 ℃; transmission line temperature: at a temperature of 280 ℃.
The mass spectrum conditions are as follows: detecting by using a triple quadrupole tandem mass spectrometer, wherein the temperature of a quadrupole is 150 ℃; adopting an EI ion source, wherein the temperature of the ion source is 250 ℃; ionization energy is 70eV; the ion detection mode is a multi-reaction detection mode; mass spectrometry parameters of 3-chloropropene, 3-bromopropene and 1-bromopropane are shown in Table 1.
TABLE 1
| Name (R) | Quantification of ions | Collision energy (eV) | Qualitative ion | Collision energy (eV) |
| 3-chloropropene | 76>41 | 6 | 41>39 | 12 |
| 3-bromopropene | 120>41 | 4 | 41>39 | 12 |
| 1-bromopropane | 124>43 | 2 | 43>41 | 6 |
1.3, carrying out methodology verification on the gas chromatography and mass spectrum conditions of the toxic impurity of the halogenated alkane gene of the pentoxifylline intermediate:
(1) Specialization inspection
Detecting blank solvent methanol, test sample solution, reference substance solution and mixed solution of the test sample and the reference substance according to detection conditions in 1.2, wherein the detection result is shown in Table 2, the chromatogram is shown in figures 1-4, the blank solvent chromatogram is shown in figure 1, the chromatogram of the reference substance solution is shown in figure 2, the chromatogram of the test sample solution is shown in figure 3, and the mixed solution of the test sample and the reference substance is shown in figure 4.
TABLE 2 results of the specificity test
From the results and the attached drawings, the blank solvent and the test solution have no interference on the detection of various impurities, and the gas chromatography-mass spectrometry combined method provided by the invention has good specificity.
(2) Detection limit and quantitative limit investigation
Accurately weighing appropriate reference substances of 3-chloropropene, 3-bromopropene and 1-bromopropane which are pentoxifylline intermediate halogenated alkane genotoxic impurities respectively, then quantitatively diluting with methanol step by step respectively, detecting according to the detection condition in 1.2, setting the analyte concentration as the quantitative limit concentration according to the signal-to-noise ratio of about 10, and continuously injecting a sample for 6 needles at the concentration; the analyte concentration at a signal-to-noise ratio of about 3 was set as the detection limit concentration, and the specific detection results are shown in tables 3 and 4 below.
TABLE 3 quantitation and detection limits test results
The data in the table show that the detection limit and the quantitative limit of the detection method for detecting the halogenated alkane genotoxic impurities 3-chloropropene, 3-bromopropylene and 1-bromopropane of the pentoxifylline intermediate are low, which indicates that the detection method has the characteristic of high sensitivity for detecting the three halogenated alkane genotoxic impurities.
TABLE 4 quantitative limit repeatability test results
The data in the table show that the Relative Standard Deviation (RSD) range of the three halogenated alkane genotoxic impurities measured by the detection method provided by the invention is between 3.51 and 6.39 percent, and the quantitative limit has good repeatability.
(3) Line survey
Taking a reference stock solution, diluting the reference stock solution with methanol, preparing a linear solution with six concentration levels within the concentration range of about 25.00-200.00ng/mL, detecting the linear solution according to the detection conditions in 1.2, measuring the peak area, drawing a standard working curve by taking the concentration of each component in the linear solution as a horizontal coordinate and the peak area as a vertical coordinate, and establishing a linear equation.
TABLE 5-1-chloropropene linearity test results
TABLE 5-2-bromopropene Linear test results
TABLE 5-3-bromopropane Linear test results
The data in the table show that the detection method provided by the invention has a wide linear range, and the genotoxic impurities of the three kinds of pentoxifylline intermediate haloalkanes have good linear relation in the range of the concentration of about 25.00-200.00ng/mL.
(4) Repeatability survey
Preparing the test solution according to the preparation method in 1.1, preparing 6 parts in parallel, and detecting according to the detection method in 1.2, wherein specific detection results are shown in the following table.
TABLE 6 results of the repeatability tests
The detection result shows that the repeated determination of 6 parts of test solution has no detection of 3-chloropropene, 3-bromopropylene and 1-bromopropane, and the method has good repeatability.
(5) Accuracy survey
Precisely weighing 9 parts of a test sample, wherein each part is 1.0g, placing the test sample into a 10mL volumetric flask respectively, then adding 0.20mL, 0.25mL and 0.30mL of the reference sample stock solutions respectively, preparing three parts in parallel at each concentration, and adding methanol to dilute the three parts to the scales respectively to obtain a recovery rate solution; the control solution and the three recovery solutions were measured under the measurement conditions of 1.2, and the recovery was calculated from the recovery (%) = (measured-original amount)/addition × 100%, and the results of the recovery are shown in the following table.
TABLE 7-1-detection of recovery of 3-chloropropene
TABLE 7-2-bromopropene recovery test results
TABLE 7-3 detection results of recovery of 1-bromopropane
The data in the table show that the method for detecting the genotoxic impurity in the haloalkanes of the pentoxifylline intermediate is within the concentration range of 1.00 to 1.50ppm, the recovery rate is 93.87 to 102.09 percent, and the RDS is less than 5 percent, which shows that the method has good accuracy.
(6) Investigation of precision
The control solution was sampled and tested under the test conditions of 1.2, and the test results are shown in the following table, wherein the test contents were calculated by performing parallel measurement 6 times.
TABLE 8 results of precision measurements
As can be seen from the data in the table, the reference substance solution is continuously detected for 6 times, and the Relative Standard Deviation (RSD) of the peak area of each impurity is 2.35% -3.51%, which indicates that the method has good precision.
(7) Durability examination
Taking a reference substance solution, then respectively fine-adjusting the temperature rise rate, the initial temperature, the injection port temperature and the carrier gas flow rate in the detection method 1.2 for detection, wherein other detection conditions are unchanged, and the durability result is shown in the following table.
TABLE 9 durability test results
From the data in the table, it can be known that the detection of each impurity is not affected by the factors of fine adjustment of the temperature rise rate, the initial temperature, the injection port temperature and the carrier gas flow rate, and the durability of the method is good.
(8) Intermediate precision review
Preparing a test solution according to the preparation method in 1.1, preparing 6 parts in parallel, detecting according to the detection method in 1.2, wherein the detection dates of the 6 parts of test solution are different, the operators are also different, and the specific detection results are shown in the following table.
TABLE 10 results of intermediate precision tests
As can be seen from the table, none of the 6 test solutions was detected, and the results were consistent with the reproducibility results, indicating that the method has good intermediate precision.
(9) Stability survey
Taking a reference substance solution and a test substance solution, standing the reference substance solution and the test substance solution at room temperature, and detecting every 0h, 2h, 4h, 6h, 8h and 24h according to the detection method in 1.2, wherein the results are shown in the following table.
TABLE 11 results of the solution stability test of the control
TABLE 12 test results of stability test of test solutions
As can be seen from the table, when the test solution is placed for 24 hours at room temperature, all impurities are not detected, and when the reference solution is placed for 24 hours at room temperature, the Relative Standard Deviation (RSD) of the peak areas of all impurities is 1.26% -2.04%, which indicates that the stability of the test solution and the reference solution is good.
As can be seen from the accompanying drawings 1 to 4 and the methodological investigation of the aspects, the detection method provided by the invention has the advantages of high detection sensitivity, low detection limit and short detection time, obviously improves the detection working efficiency, has accurate and reliable detection result and good linear relation, simultaneously has good precision and durability, can monitor the quality stability of the pentoxifylline intermediate, and further provides guarantee and basis for the clinical medication safety of the pentoxifylline.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. The method for detecting the halogenated alkane genotoxic impurities in the pentoxifylline intermediate is characterized by comprising the following steps of: preparing a solution to be detected by using an organic solvent, and detecting toxic impurities of halogenated alkane genes of the pentoxifylline intermediate by using a gas chromatography-mass spectrometry combined method; the pentoxifylline intermediate is 5, 6-dihydro-3-ethoxycarbonyl-2-methyl-4H-pyran, and the haloalkane genotoxic impurities comprise 3-chloropropene, 3-bromopropylene and 1-bromopropane;
the chromatographic conditions of the gas chromatography include: the temperature-raising procedure of the gas chromatography is as follows: the initial temperature is 37 to 43 ℃, the temperature is maintained for 3min, the temperature is raised to 127 to 133 ℃ at the speed of 9.5 to 10.5 ℃/min, the temperature is raised to 177 to 183 ℃ at the speed of 24.5 to 25.5 ℃/min, and the fixing solution of a capillary chromatographic column is 6wt% of cyanopropylphenyl-94 wt% of polydimethylsiloxane;
the conditions of the mass spectrum include: detecting by adopting a triple quadrupole tandem mass spectrometer, wherein the temperature of a quadrupole is 150 ℃; EI ion source is adopted, and the temperature of the ion source is 200 to 300 ℃.
2. The method for detecting the toxic impurities of the halogenated alkane genes in the pentoxifylline intermediate as claimed in claim 1, wherein the solution to be detected comprises a reference solution, and the concentrations of the 3-chloropropene, the 3-bromopropene and the 1-bromopropane in the reference solution are all 25.00-200.00ng/ml.
3. The method of claim 1, wherein the chromatographic conditions of the gas chromatograph further comprise: the sample introduction mode is divided sample introduction, and the division ratio is 10:1.
4. the method of claim 1, wherein the chromatographic conditions of the gas chromatograph further comprise: the length of the capillary chromatographic column is 15 to 75m, the inner diameter is 0.15 to 0.53mm, and the thickness of the stationary phase coating liquid film is 0.84 to 3.0 mu m.
5. The method of claim 1, wherein the chromatographic conditions of the gas chromatograph further comprise: helium is used as a carrier gas, and the flow rate of the carrier gas is 0.9 to 1.1mL/min.
6. The method of claim 1, wherein the chromatographic conditions of the gas chromatograph further comprise: the temperature of a sample inlet is 217 to 223 ℃; the sample injection amount is 0.9 to 1.1 mu L.
7. The method of claim 1, wherein the mass spectrometric conditions further comprise: the ion detection mode is a multi-reaction detection mode.
8. The method of claim 1, wherein the mass spectrometric conditions further comprise:
the quantitative ion of 3-chloropropene is 76 & gt 41, the collision energy of the quantitative ion is 6 eV, the collision energy of the qualitative ion is 41 & gt 39, and the collision energy of the qualitative ion is 12 eV;
the quantitative ion of the 3-bromopropylene is more than 120 and more than 41, the collision energy of the quantitative ion is 4 eV, the qualitative ion is more than 39, and the collision energy of the qualitative ion is 12 eV;
the quantitative ion of the 1-bromopropane is 124 & gt 43, the collision energy of the quantitative ion is 2 eV, the qualitative ion is 43 & gt 39, and the collision energy of the qualitative ion is 6 eV.
9. The method of claim 1, wherein the mass spectrometric conditions further comprise: the ionization energy was 70eV.
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