CN111272897A - Method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid - Google Patents
Method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid Download PDFInfo
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Abstract
The invention discloses a method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid. The method takes Acclaim RSLC 120C 18 as a chromatographic column, adopts an LC-MS detection method to perform qualitative and quantitative analysis on impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid, and performs methodology verification. The invention establishes a qualitative and quantitative method for impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid for the first time, and is convenient for controlling the quality of pemetrexed acid, thereby improving the medication safety of pemetrexed disodium.
Description
Technical Field
The invention relates to a detection method of 2 impurities (2-amino-4, 6-dihydroxypyrimidine and 4-amino-2, 6-dihydroxypyrimidine) in pemetrexed acid, belonging to the technical field of medicines.
Background
Pemetrexed acid is an intermediate of Pemetrexed Disodium, which is a new anticancer drug introduced by the li corporation, and is approved by the FDA in the united states for the treatment of malignant pleural mesothelioma in 2 months in 2004, and is approved by the FDA in the same 10 months in the same year as a second-line treatment of locally advanced lung cancer or metastatic non-small cell lung cancer. Currently, it is marketed in 60 countries and regions of the world. Pemetrexed disodium in combination with cisplatin is used for the treatment of inoperable malignant pleural mesothelioma. Pemetrexed enters the cell via a folate-carrying carrier and a folate-binding protein transport system on the cell membrane. Once pemetrexed enters the cell, it is localized to folylGrainThe amino acid synthetase is converted into polyglutamic acid by the action of the enzyme. Polyglutamic acid remains in cells as inhibitors of thymidylate synthase and glycinamide nucleotidyl transferase, but at very low concentrations in normal tissues. The half-life of the polyglutamated metabolite in the tumor cells is prolonged, so that the action time of the drug in the tumor cells is prolonged.
2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine are byproducts in the production process of pemetrexed acid, and both have warning structures and can have genetic toxicity, so a detection method of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid is formulated, and the quality of pemetrexed acid is controlled. However, no report about the content detection method of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid exists at present through search.
Pemetrexed acid, english name: pemetrexed discodium, molecular formula: c20H21N5O6(ii) a Molecular weight: 427.417, the structural formula is shown below:
2-amino-4,6-dihydroxypyrimidine, english name: 2-amino-4,6-dihydroxypyrimidine, molecular formula: c4H5N3O2(ii) a Molecular weight: 127.10, the structural formula is shown below:
4-amino-2,6-dihydroxypyrimidine, english name: 4-amino-2,6-dihydroxypyrimidine, molecular formula: c4H5N3O2(ii) a Molecular weight: 127.10, the structural formula is shown below:
disclosure of Invention
Aiming at the problems, the invention provides a method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid as impurities for the first time. The method uses Acclaim RSLC 120C 18 as a chromatographic column, adopts an LC-MS detection method to perform qualitative and quantitative analysis on impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid, and performs methodology verification. Experiments prove that the method has the advantages of strong specificity, rapidness, sensitivity, accuracy and the like, and can reliably carry out qualitative and quantitative analysis on the impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid.
The technical scheme of the invention is as follows: a method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid is characterized in that a pemetrexed acid sample is dissolved (acetonitrile-water (1:1) is adopted for dissolving), and then an LC-MS detection method is adopted for qualitatively and quantitatively detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine which are impurities in pemetrexed acid.
Wherein, the chromatographic conditions are as follows:
a chromatographic column: acclaim RSLC 120C 18 (2.0X 100mm, 2.2 μm), flow rate: 0.2ml/min, column temperature: 20-50 ℃, sample injection amount: 2 μ l, mobile phase: 0.1% aqueous acetic acid-acetonitrile. The gradient elution conditions are shown in table 1.
TABLE 1 gradient elution Table
Gradient elution conditions are preferred, as shown in table 3 below.
The mass spectrum conditions are as follows: an ion source: electrospray ionization source (ESI), positive ion mode: selection of quantitative (SRM) mode, spray voltage (IS): 3500V; the evaporation temperature is 275 ℃; sheath Gas (Gas 1): 35 Arb; auxiliary Gas (Gas 2): 7 Arb;
ion transport Tube temperature (Ion Transfer Tube Temp): 325 ℃; the ion pairs used for quantitative analysis were m/z128.08 → m/z60.17 (2-amino-4, 6-dihydroxypyrimidine) and m/z128.12 → m/z68.08 (4-amino-2, 6-dihydroxypyrimidine) with the mass spectrometry conditions as shown in Table 2.
TABLE 2 Mass Spectrometry Condition Table
Furthermore, the invention adopts an external standard method to measure 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid.
The invention has the advantages that:
1. 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine are byproducts in the production process of pemetrexed acid, and have warning structures. The invention establishes a detection method for impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid for the first time, and is convenient for controlling the quality of pemetrexed acid, thereby improving the medication safety of pemetrexed disodium.
2. Good separation effect and high sensitivity
In the high performance liquid chromatography, the retention time of 2-amino-4,6-dihydroxypyrimidine in a mixed solution is slightly different from that of a control solution and is interfered by a foreign peak, the retention time cannot be improved by adjusting acidity, using buffer salt, using an ion pair reagent and replacing a chromatographic column, and in view of the fact that the interference of the foreign peak can be eliminated by a quantitative mode of mass spectrometry, the contents of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid are controlled by using a mass spectrometry with extremely high sensitivity. The LC-MS detection method is established for the first time, the optimization method is carried out, the optimization results of the 2-amino-4,6-dihydroxypyrimidine and the 4-amino-2,6-dihydroxypyrimidine are shown in the figure 1-2, and the optimization method enables the two components and pemetrexed acid to be well separated. As can be seen from FIGS. 3-6: 2-amino-4,6-dihydroxypyrimidine RT is 1.48 min; 4-amino-2,6-dihydroxypyrimidine RT was 1.53 min; pemetrexed acid peak RT is 5.43min, and the separation effect of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine from pemetrexed acid is good.
3. The method has strong specificity, and is rapid, sensitive and accurate
Experiments prove that the method has the advantages of strong specificity (specially aiming at 2-amino-4,6-dihydroxypyrimidine and 4-amino-2, 6-dihydroxypyrimidine), rapidness, sensitivity (the detection limits are 0.1671ng/ml and 0.1865ng/ml respectively, and the quantification limits are 0.3341ng/ml and 0.3730ng/ml respectively), accuracy (94.29% -104.76% and 87.18% -100.00%), and the like, and can reliably carry out qualitative and quantitative analysis on the contents of the 2-amino-4,6-dihydroxypyrimidine and the 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid.
Drawings
FIG. 1 is a graph of the ion and collision energies of 2-amino-4,6-dihydroxypyrimidine optimizers;
FIG. 2 is a graph of 4-amino-2,6-dihydroxypyrimidine optimizer ions and collision energies;
FIG. 3 shows mass spectra of 2-amino-4,6-dihydroxypyrimidine (RT: 1.48min) and 4-amino-2,6-dihydroxypyrimidine (RT: 1.53 min);
FIG. 4 is a graph of a pemetrexed acid sample spectrum (RT: 5.43 min);
FIG. 5 is a graph of 2-amino-4,6-dihydroxypyrimidine peak extractions;
FIG. 6 is a graph of 4-amino-2,6-dihydroxypyrimidine peak extraction.
Detailed Description
Example 1
1 instruments and materials
1.1 Instrument: a triple quadrupole liquid chromatography mass spectrometer (Thermo Ultimate 3000-TSQ Quantiva);
1.2 reagent: acetonitrile is chromatographic grade, and water is ultrapure water.
2 methods and results
2.1 chromatographic and Mass Spectrometry conditions
A chromatographic column: acclaim RSLC 120C 18 (2.0X 100mm, 2.2 μm), flow rate: 0.2ml/min, column temperature:
20-50 ℃, sample injection amount: 2 μ l, mobile phase: 0.1% aqueous acetic acid-acetonitrile. The gradient elution conditions are shown in Table 3.
TABLE 3 gradient elution Table
| Time (min) | 0.1% aqueous acetic acid (%) | Acetonitrile (%) |
| 0 | 85 | 15 |
| 3 | 85 | 15 |
| 4 | 50 | 50 |
| 8 | 50 | 50 |
| 9 | 85 | 15 |
| 20 | 85 | 15 |
The mass spectrum conditions are as follows: an ion source: electrospray ionization source (ESI), negative ion mode: selection of quantitative (SRM) mode, spray voltage (IS): 2500V; the evaporation temperature is 275 ℃; sheath Gas (Gas 1): 35 Arb; auxiliary Gas (Gas 2): 7 Arb;
ion transport Tube temperature (Ion Transfer Tube Temp): 325 ℃; the ion pairs used for quantitative analysis were m/z128.08 → m/z60.17 (2-amino-4, 6-dihydroxypyrimidine) and m/z128.12 → m/z68.08 (2-amino-4, 6-dihydroxypyrimidine), and the mass spectrometry conditions are shown in Table 4 and FIGS. 1-2.
TABLE 4 Mass Spectrometry Condition Table
| Name (R) | Parent ion (m/z) | Ionic acid (m/z) | Collision energy (V) | Radio frequency lens (V) |
| 2-amino-4,6-dihydroxypyrimidine | 128.08 | 60.17 | 17 | 56 |
| 4-amino-2,6-dihydroxypyrimidine | 128.12 | 68.08 | 25 | 61 |
2.2 preparation of the solution
2.21 preparation of control solutions
Respectively weighing about 1mg of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as reference by a reduction method, placing the weighed materials into a same 100ml measuring flask, adding acetonitrile-water (1:1) for ultrasonic dissolution, diluting to a scale, and shaking up; precisely measuring 3ml, placing in a 100ml measuring flask, diluting to scale with acetonitrile-water (1:1), and shaking; precisely measuring 1ml, placing in a 50ml measuring flask, diluting to scale with acetonitrile-water (1:1), and shaking.
2.22 preparation of Linear solution
Respectively weighing about 1mg of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as reference by a reduction method, placing the weighed materials into a same 100ml measuring flask, adding acetonitrile-water (1:1) for ultrasonic dissolution, diluting to a scale, and shaking up; precisely measuring 3ml, placing in a 100ml measuring flask, diluting to scale with acetonitrile-water (1:1), shaking, and diluting to 50ml with 0.2ml, 0.6ml, 0.8ml, 1.0ml and 1.4ml, wherein each solution is 3ppm, 9ppm, 12ppm, 15ppm and 21 ppm.
2.23 preparation of sample solutions
Test solution: taking six parts of pemetrexed acid (about 20mg (calculated according to dry products)) and precisely weighing, placing the six parts into a 50ml measuring flask, adding acetonitrile-water (1:1) for ultrasonic dissolution, diluting to a scale, and shaking up. The repeatability of the method was calculated. The same sample was measured on different days and the intermediate precision of the method was calculated.
Preparing a sample, adding test sample solutions of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine reference substance solutions with different concentrations, and calculating the accuracy of the method.
2.3 detection
Precisely measuring the reference substance solution, the linear solution and the sample solution, respectively injecting samples, performing LC-MS detection according to the chromatographic and mass spectrum conditions shown in 2.1, recording the spectrum, and calculating the peak area. The retention times of the three solutions are shown in figures 3-4, respectively. As can be seen from fig. 3-4: 2-amino-4,6-dihydroxypyrimidine RT is 1.48 min; 4-amino-2,6-dihydroxypyrimidine RT was 1.53 min; pemetrexed acid peak RT is 5.43min, 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine have good separation effect with the pemetrexed acid, and other impurities do not interfere with the determination.
3 validation of analytical methods
3.1 Linear relationship
Taking the serial diluted reference substance solution for LC-MS measurement, and drawing a standard working curve by taking the concentration of the 2-amino-4,6-dihydroxypyrimidine and the 4-amino-2,6-dihydroxypyrimidine as abscissa and the area as ordinate. The linear equation of the 2-amino-4,6-dihydroxypyrimidine is that y is 16284369.9828x-3457.7447, and r is 0.9991; the linear equation of 4-amino-2,6-dihydroxypyrimidine is 28451991.6678x-4392.0740, r is 0.9994. Continuously sampling a 2-amino-4,6-dihydroxypyrimidine solution with the concentration of 0.006960 mu g/ml and 4-amino-2,6-dihydroxypyrimidine with the concentration of 0.007770 mu g/ml for six times, wherein the peak area RSD obtained by the 2-amino-4,6-dihydroxypyrimidine is 2.4 percent, and the retention time RSD is 0 percent; the peak area RSD obtained for 4-amino-2,6-dihydroxypyrimidine was 3.7%, and the retention time RSD was 0.3%.
3.2 repeatability and intermediate precision
And taking six solutions prepared from the same pemetrexed acid sample to perform a repeatability experiment and an intermediate precision experiment, wherein 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine are not detected in the pemetrexed acid sample.
3.3 accuracy and durability
Preparing a sample, adding test sample solutions of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine reference substance solutions with different concentrations, and calculating the accuracy of the method. The results are shown in tables 5-1 and 5-2.
TABLE 5-12-amino-4, 6-dihydroxypyrimidine accuracy results
TABLE 5-24-amino-2, 6-dihydroxypyrimidine accuracy results
3.4 durability: taking the reference solution and the test solution, repeatedly injecting the sample within 24 hours, and showing that the reference solution and the test solution are both stable. 3.5 detection limit: the detection Limit (LOD) of the method is the sample injection concentration of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine when the signal-to-noise ratio S/N is more than 3 times, and the sample injection concentrations are respectively 0.1671ng/ml and 0.1865ng/ml through calculation.
3.6 limit of quantitation: the quantitative Limit (LOQ) of the method is that the sample injection concentrations of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine when the signal-to-noise ratio S/N is more than 10 times are respectively 0.3341ng/ml and 0.3730ng/ml by calculation.
Discussion 4
The content of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid cannot be accurately controlled by using an ultraviolet detector and a differential refraction detector in a high performance liquid chromatograph. The LC-MS detection method is established and optimized, so that the two components can be well separated from a test sample (as shown in figures 3-6). Experiments prove that the method has the advantages of strong specificity, rapidness, sensitivity, accuracy and the like, and can reliably carry out qualitative and quantitative analysis on the contents of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid.
The 2-amino-4,6-dihydroxypyrimidine and the 4-amino-2,6-dihydroxypyrimidine have warning structures. Based on the requirements of ICH M7, we set the control limit to 15ppm or less.
Example 2: detection of actual samples
1) Control solution: respectively weighing about 1mg of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as reference by a reduction method, placing the weighed materials into a same 100ml measuring flask, adding acetonitrile-water (1:1) for ultrasonic dissolution, diluting to a scale, and shaking up; precisely measuring 3ml, placing in a 100ml measuring flask, diluting to scale with acetonitrile-water (1:1), and shaking; precisely measuring 1ml, placing in a 50ml measuring flask, diluting to scale with acetonitrile-water (1:1), and shaking.
2) Test solution: taking about 20mg (calculated according to dry product), precisely weighing, placing in a 50ml measuring flask, adding acetonitrile-water (1:1), ultrasonically dissolving, diluting to scale, and shaking up.
3) Taking the test solution and the reference solution prepared in the steps 1) and 2), and performing LC-MS detection by using instruments and reagents which are completely the same as those in the example 1 and under the chromatographic and mass spectrum conditions shown in 2.1.
4) And calculating the contents of the impurities 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in the pemetrexed acid according to an external standard method.
Three batches were tested using the method described above and the results are shown in table 6 below.
TABLE 6 test results of products
| |
1 | 2 | 3 |
| 2-amino-4,6-dihydroxypyrimidine (ppm) | Not detected out | Not detected out | Not detected out |
| 4-amino-2,6-dihydroxypyrimidine ppm | Not detected out | Not detected out | Not detected out |
Claims (8)
1. A method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid is characterized in that after a pemetrexed acid sample is dissolved, an LC-MS detection method is adopted to qualitatively and quantitatively detect 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine which are impurities in pemetrexed acid;
wherein, the chromatographic conditions are as follows: acclaim RSLC 120C 18 chromatography column, mobile phase: 0.1% aqueous acetic acid-acetonitrile.
2. The method of claim 1, wherein the gradient elution of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine is performed by a mobile phase, the gradient elution conditions are shown in the following table,
。
3. The method of claim 2, wherein the gradient elution conditions are as shown in the following table,
。
4. The method of claim 1, wherein the chromatographic column specification is as follows: 2.0X 100mm, 2.2 μm; flow rate: 0.2ml/min, column temperature: 20-50 ℃, sample injection amount: 2 μ l.
5. The method of claim 1, wherein the mass spectrometric conditions comprise: an ion source: electrospray ionization source ESI, positive ion mode: selecting a quantitative SRM mode; the ion pair for quantitative analysis of 2-amino-4,6-dihydroxypyrimidine was m/z128.08 → m/z60.17, and the ion pair for quantitative analysis of 4-amino-2,6-dihydroxypyrimidine was m/z128.12 → m/z 68.08.
6. The method of claim 5, wherein the evaporation temperature is 275 ℃ for the detection of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid; sheath gas pressure: 35 Arb; auxiliary gas pressure: 7 Arb; ion transfer tube temperature: 325 ℃.
7. The method of claim 5, wherein the ratio of the spray voltage: 3500V; radio frequency Lens RF Lens: the 2-amino-4,6-dihydroxypyrimidine is 56V, 4-amino-2,6-dihydroxypyrimidine 61V; collision energy CE: 2-amino-4,6-dihydroxypyrimidine 17V, 4-amino-2,6-dihydroxypyrimidine 25V.
8. The method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid according to any one of claims 1 to 7, wherein the content of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as impurities in pemetrexed acid is determined by an external standard method.
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