CN111272897B - Detection method of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid - Google Patents
Detection method of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid Download PDFInfo
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- 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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- G—PHYSICS
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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
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
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- G01—MEASURING; TESTING
- 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
- G01N30/02—Column chromatography
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
- G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
Abstract
The invention discloses a detection method of 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 detection 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 proposed by the li corporation, approved by the FDA in the united states in 2 months 2004 in combination with cisplatin for the treatment of a rare cancer, malignant pleural mesothelioma, and approved by the FDA in the same 10 months in the same year in a rapid approval manner 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 at She XianduoGrainThe 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 polyglutaminated metabolites in tumor cells is prolonged, and thusThe action time of the medicine in 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 after search.
Pemetrexed acid, english name: pemetrexed discodium, molecular formula: c 20 H 21 N 5 O 6 (ii) a Molecular weight: 427.417, having the formula:
2-amino-4,6-dihydroxypyrimidine, english name: 2-amino-4,6-dihydroxypyramidine, molecular formula: c 4 H 5 N 3 O 2 (ii) a Molecular weight: 127.10, the structural formula is as follows:
4-amino-2,6-dihydroxypyrimidine, english name: 4-amino-2,6-dihydroxypyramidine, molecular formula: c 4 H 5 N 3 O 2 (ii) a Molecular weight: 127.10, the structural formula is as follows:
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 qualitatively and quantitatively detect 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine which are impurities 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 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine serving as impurities 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): 35Arb; auxiliary Gas (Gas 2): 7Arb;
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) and the mass spectrometry conditions are 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 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine serving as impurities in pemetrexed acid for the first time, and facilitates the control of 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 mixed peak, the retention time cannot be improved by adjusting acidity, using buffer salt, using an ion pair reagent and replacing a chromatographic column, and the interference of the mixed solution by the mixed solution can be eliminated by a quantitative mode of a mass spectrometry, so that the contents of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid can be controlled by using a mass spectrometry with extremely high sensitivity. The invention establishes an LC-MS detection method for the first time, optimizes the method, and obtains the optimized results of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as shown in figures 1-2, and the optimized method enables the two components and pemetrexed acid to be well separated. As can be seen from fig. 3 to 6: 2-amino-4,6-dihydroxypyrimidine RT is 1.48min; 4-amino-2,6-dihydroxypyrimidine RT is 1.53min; 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.
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 perform qualitative and quantitative analysis on the contents of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid.
Drawings
FIG. 1 is a graph of the ion and collision energies for 2-amino-4,6-dihydroxypyrimidine optimizer;
FIG. 2 is a graph of 4-amino-2,6-dihydroxypyrimidine optimizer ions and collisional energies;
FIG. 3 shows mass spectra of 2-amino-4,6-dihydroxypyrimidine (RT: 1.48 min) 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 extraction;
FIG. 6 is a graph of 4-amino-2,6-dihydroxypyrimidine peak extraction.
Detailed Description
Example 1
1 instruments and materials
1.1 Instrument: triple quadrupole LC-MS (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): 35Arb; auxiliary Gas (Gas 2): 7Arb;
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 fig. 1-2.
TABLE 4 Mass Spectrometry Condition Table
| Name (R) | Parent ion (m/z) | Sub-ion (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 about 1mg of 4-amino-2,6-dihydroxypyrimidine by a decrement method, placing the two reference samples into the 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 measure 1ml, place in a 50ml measuring flask, dilute to scale with acetonitrile-water (1:1), and shake well.
2.22 preparation of Linear solution
Respectively weighing about 1mg of 2-amino-4,6-dihydroxypyrimidine and about 1mg of 4-amino-2,6-dihydroxypyrimidine by a decrement method, placing the two reference samples into the 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 21ppm.
2.23 preparation of sample solutions
Test solution: taking six parts of pemetrexed acid (about 20mg (calculated according to dry products), precisely weighing, placing in a 50ml measuring flask, adding acetonitrile-water (1:1), ultrasonically dissolving, diluting to scale, and shaking uniformly. 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 a sample solution 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 1.48min; 4-amino-2,6-dihydroxypyrimidine RT is 1.53min; 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 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine as abscissa and the area as ordinate as the result. 2-amino-4,6-dihydroxypyrimidine linear equation y =16284369.9828x-3457.7447, r =0.9991; the linear equation for 4-amino-2,6-dihydroxypyrimidine is y =28451991.6678x-4392.0740, r =0.9994. Continuously feeding 2-amino-4,6-dihydroxypyrimidine solution with the concentration of 0.006960 mug/ml and 4-amino-2,6-dihydroxypyrimidine with the concentration of 0.007770 mug/ml for six times, wherein the peak area RSD obtained by 2-amino-4,6-dihydroxypyrimidine is =2.4%, and the retention time RSD is =0%; the peak area RSD obtained for 4-amino-2,6-dihydroxypyrimidine =3.7% and retention time RSD =0.3%.
3.2 repeatability and intermediate precision
And (3) carrying out a repeatability experiment and an intermediate precision experiment on six solutions prepared from the same pemetrexed acid sample, 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 a sample solution 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 5-1-amino-4,6-dihydroxypyrimidine accuracy results
TABLE 5-2-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 0.1671ng/ml and 0.1865ng/ml respectively through calculation.
3.6 limit of quantitation: the quantitative Limit (LOQ) of the method is that the 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.
4 discussion of
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.
2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine both 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 about 1mg of 4-amino-2,6-dihydroxypyrimidine by a decrement method, placing the two reference samples into the 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 measure 1ml, place in a 50ml measuring flask, dilute to the mark with acetonitrile-water (1:1), shake up.
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 uniformly.
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 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine serving as impurities 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) | Undetected | Not detected out | Not detected out |
| 4-amino-2,6-dihydroxypyrimidine ppm | Undetected | Undetected | Not detected out |
Claims (2)
1. A detection method of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid is characterized in that a pemetrexed acid sample is dissolved by acetonitrile and water with the volume ratio of 1:1, and then an LC-MS detection method is adopted to qualitatively and quantitatively detect impurities of 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid;
wherein, the chromatographic conditions are as follows: acclaim RSLC 120C 18 chromatographic column, chromatographic column specification: 2.0X 100mm,2.2 μm; flow rate: 0.2ml/min, column temperature: 20-50 ℃, sample injection amount: 2 mul; mobile phase: 0.1% aqueous acetic acid-acetonitrile;
the gradient elution conditions are shown in the following table,
；
The mass spectrum conditions are as follows: an ion source: electrospray ionization source ESI, positive ion mode: selecting a quantitative SRM mode; spraying voltage: 3500V; the evaporation temperature was 275 ℃; sheath gas pressure: 35Arb; auxiliary gas pressure: 7Arb; ion transport tube temperature: 325 ℃;
2-amino-4,6-dihydroxypyrimidine ion pair for quantitative analysis is m/z128.08 → m/z60.17, 4-amino-2,6-dihydroxypyrimidine ion pair for quantitative analysis is m/z128.12 → m/z68.08; radio frequency Lens RF Lens: 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.
2. The method for detecting 2-amino-4,6-dihydroxypyrimidine and 4-amino-2,6-dihydroxypyrimidine in pemetrexed acid according to claim 1, 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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Address after: 251400 No. 12, Taixing East Street, Jibei Economic Development Zone, Jiyang District, Jinan City, Shandong Province Applicant after: Shandong Baoyuan Pharmaceutical Co.,Ltd. Address before: Strong in Jiyang County of Ji'nan City, 251400 North Street, Shandong Province Economic Development Zone Applicant before: SHANDONG BOYUAN PHARMACEUTICAL Co.,Ltd. |
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| GR01 | Patent grant | ||
| GR01 | Patent grant |