CN114235982A - Method for analyzing carbon tetrachloride solvent residue in linagliptin by gas chromatography - Google Patents
Method for analyzing carbon tetrachloride solvent residue in linagliptin by gas chromatography Download PDFInfo
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Abstract
The invention discloses a method for analyzing carbon tetrachloride solvent residue in linagliptin by using gas chromatography. Diluting linagliptin with N, N-dimethylformamide to obtain a test solution, and weighing quantitative carbon tetrachloride to prepare a reference solution; and then respectively injecting the sample solution and the reference substance solution in a headspace manner for gas chromatography detection, wherein the gas chromatography detection is used for detecting the residue of carbon tetrachloride solvent in linagliptin and controlling the detection limit of carbon tetrachloride. The invention can detect the concentration of carbon tetrachloride to be 0.002 mug/mL at the lowest limit, thus greatly improving the detection sensitivity; meanwhile, on the premise of meeting the requirements, the detection limit concentration of carbon tetrachloride is controlled to be less than or equal to 4ppm, and the method meets the detection requirements on system applicability and accuracy.
Description
Technical Field
The invention belongs to the technical field of analytical chemistry. More particularly, the invention relates to a method for analyzing the residual carbon tetrachloride solvent in linagliptin by gas chromatography.
Background
The linagliptin compound is a main component of a medicine with the trade name of linagliptin tablet, and has the chemical name of 8- [ (3R) -3-amino-1-piperidyl ] -7- (2-butynyl-1) -3, 7-dihydro-3-methyl-1- [ (4-methyl-2-quinazolinyl) methyl ] -1H-purine-2, 6-dione; the medicine synthesized by the compound belongs to a novel selective dipeptidyl peptidase-4 (DPP-4) inhibitor and can be used for treating type II diabetes.
Currently, the organic solvent dichloromethane is often used in the synthesis process route of linagliptin or analogs thereof, and carbon tetrachloride residue can be caused in the reaction. Carbon tetrachloride is an organic compound of the formula CCl4Molecular weight is 153.84, it is a colorless transparent liquid, volatile, toxic, has chloroform smell, and tastes sweet. As the prior art discloses a preparation method of an intermediate of linagliptin or an analogue thereof and linagliptin or an analogue thereof, wherein an organic solvent is prepared and synthesized by adopting dichloromethane most preferably; carbon tetrachloride residue is easily caused.
In the detection research related to linagliptin, the preparation synthesis of linagliptin and the content detection of linagliptin are mainly focused, and as the prior art discloses a method for determining the content of linagliptin in linagliptin bulk drug, the linagliptin bulk drug is analyzed by adopting a high performance liquid chromatography, so that the drug effect, the quality and the pharmaceutical safety of the linagliptin bulk drug are effectively controlled. However, the carbon tetrachloride residue in the linagliptin original drug is strictly limited, and the research and analysis on the carbon tetrachloride residue caused by adopting dichloromethane in the preparation synthesis and use of linagliptin are not shown, so that the strict limit control on the carbon tetrachloride residue of linagliptin has important practical value on the production of medicines and the quality control of products.
Disclosure of Invention
The invention aims to provide a gas chromatography analysis method for carbon tetrachloride solvent residue in linagliptin, which can accurately detect the carbon tetrachloride residue in linagliptin within a detection limit range and can strictly control the carbon tetrachloride residue limit in linagliptin.
The above purpose of the invention is realized by the following technical scheme:
a gas chromatography analysis method for residual carbon tetrachloride solvent in linagliptin comprises the following steps:
preparing a reference substance solution: weighing quantitative carbon tetrachloride and preparing by adopting a diluent;
preparing a solution of a preparation formula: weighing a certain amount of linagliptin in a headspace bottle, adding a diluent, sealing by a gland, dissolving and shaking uniformly;
and detecting and analyzing the residue of the carbon tetrachloride solvent in the sample by adopting a headspace sampling method and adopting gas chromatography.
Further, the diluent is: n, N-dimethylformamide.
Further, the chromatographic column adopted by the gas chromatography detection is as follows: BD-1 capillary columns or other similar packed chromatographic columns such as: HP-1, Ultra-1, SPB-1, CP-Sil 5CB Low Black/MS, Rtx-1, BP-1, OV-101, 007-1(MS), SP-2100, SE-30, CP-Sil 5CB MS, ZB-1, AT-1, MDN-1, or ZB-1.
Preferably, the chromatographic column is: BD-1 capillary column (30m 0.32mm 1.5 μm).
Further, the initial column temperature in the gas chromatography detection is 30-50 ℃, the initial column temperature is maintained for 5-15 min, the temperature is increased at the rate of 10-30 ℃ per minute to 200-250 ℃, and the initial column temperature is maintained for 1-10 min.
Preferably, the initial column temperature in the gas chromatography assay is 40 ℃ for 9min, and the temperature is raised at a rate of 20 ℃ per minute to 220 ℃ for 3 min.
Furthermore, an ECD detector is adopted as a detector in the gas chromatography detection, and the temperature of the detector is 200-400 ℃.
Preferably, the detector temperature is 300 ℃.
Further, carrier gas in the gas chromatography detection is high-purity nitrogen, high-purity helium or high-purity hydrogen, and the split ratio is 5-50: 1.
Preferably, the carrier gas is high purity nitrogen gas with a split ratio of 50: 1.
Furthermore, the sample injection volume in the gas chromatography detection is 0.1-1 ml.
Preferably, the injection volume is 0.2 ml.
Further, the temperature of a sample inlet in the gas chromatography detection is 100-300 ℃.
Preferably, the sample port temperature is 250 ℃.
Further, the parameters of the headspace sample injector in the gas chromatography detection are as follows: the balance temperature is 50-100 ℃, the balance time is 20-40 min, the temperature of a sampling needle is 60-120 ℃, the temperature of a transmission line is 80-120 ℃, the GC cycle time is 30-60 min, the pressurization time is 1-10 min, the needle pulling time is 0.1-2 min, and the carrier gas pressure is 10-30 psi.
Preferably, the parameters of the headspace sampler are: the balance temperature is 55 ℃, the balance time is 35min, the sampling needle temperature is 85 ℃, the transmission line temperature is 95 ℃, the GC cycle time is 31min, the pressurization time is 3min, the needle pulling time is 0.5min, and the carrier gas pressure is 20 psi.
Further, the concentration of the test solution is 1-100 mg/ml.
More preferably, the concentration of the sample solution is 40-60 mg/ml.
More preferably, the concentration of the test solution is 50 mg/ml.
Preferably, the concentration of the control solution is 0.0001-0.001 mg/mL.
Preferably, the concentration of the control solution is 0.0002 mg/mL.
Preferably, the concentration of the detection limit solution is 0.000001-0.00001 mg/mL.
Preferably, the detection limit solution concentration is 0.000002 mg/mL.
Most preferably, the chromatographic conditions are as follows:
the invention has the following beneficial effects:
according to the method, the sample is diluted by the N, N-dimethylformamide solvent, and the gas chromatography detection is carried out by adopting the headspace sampling mode, so that the limit of the residual amount of carbon tetrachloride in linagliptin can be accurately and reliably detected, the concentration of the carbon tetrachloride can be detected to be 0.002 mu g/mL at the lowest limit by using the method, and the detection sensitivity is greatly improved; meanwhile, on the premise of meeting the requirement, the concentration of the detection limit of carbon tetrachloride is controlled to be less than or equal to 4ppm, when the detection result is smaller than the carbon tetrachloride peak area of the detection limit solution, the detection output result is not detected, and the carbon tetrachloride residual limit in the medicine is met, and the method also meets the detection requirement on system applicability and accuracy, so the method can be used for accurately detecting the carbon tetrachloride residual in the linagliptin within the detection limit range well, and has important practical value for the quality control of the linagliptin medicine.
Drawings
Fig. 1 is a blank solution chromatogram for system suitability verification.
FIG. 2 is a chromatogram of a detection limit solution for system suitability verification.
FIG. 3 is a first pin chromatogram of a system suitability verification control solution.
FIG. 4 is a second chromatogram for a system suitability verification control solution.
FIG. 5 is a third chromatogram for a system suitability verification control solution.
FIG. 6 is a chromatogram of a proprietary validation control solution.
FIG. 7 is a chromatogram of a solution of a specific assay sample.
FIG. 8 is a chromatogram of a labeling solution added to a specific assay sample.
FIG. 9 is a first pin chromatogram of a detection limit verifying solution.
Fig. 10 is a second chromatogram of a detection limit verifying detection limit solution.
FIG. 11 is a third chromatogram of a detection limit verifying solution.
FIG. 12 is a first chromatogram of a control solution for measuring residual carbon tetrachloride solvent in linagliptin.
FIG. 13 is a second chromatogram of a control solution for measuring residual carbon tetrachloride solvent in linagliptin.
FIG. 14 is a third chromatogram of a control solution for measuring residual carbon tetrachloride solvent in linagliptin.
FIG. 15 is a chromatogram of a test solution-1 for measuring the residual carbon tetrachloride solvent in linagliptin.
FIG. 16 is a chromatogram of a test solution-2 for measuring the residual carbon tetrachloride solvent in linagliptin.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
The instrument comprises the following steps: a gas chromatograph (ECD detector), an Agilent headspace sampler, an electronic balance;
reagent: carbon tetrachloride (spectral grade), N-dimethylformamide dmf (hplc);
and (3) testing the sample: linagliptin drug substance (purchased from boston sun pharmaceutical co., ltd).
Example 1 System suitability verification
Firstly, solution preparation:
blank solution: precisely measuring 5.0mL DMF to 20mL headspace bottles, sealing and shaking up;
control stock solutions: (1) accurately weighing 100mg of carbon tetrachloride into a 100mL measuring flask, releasing to the scale with DMF, and shaking up; (2) precisely measuring 1.0mL of the solution in the step (1) into a 50mL measuring flask, releasing to the scale with DMF, and shaking up; (3) precisely measuring 1.0mL of the solution in the step (2) into a 100mL measuring flask, releasing the solution to the scale with DMF, and shaking up to obtain a control stock solution of 0.0002 mg/mL;
control solution: precisely transferring 5.0mL of the control stock solution into a 20mL headspace bottle, and capping to obtain the product with the concentration of 0.0002 mg/mL;
detection limiting solution: (1) precisely transferring 1mL of the control stock solution to a 100mL measuring flask, diluting the control stock solution to a scale with DMF, and shaking up to obtain the compound preparation with the concentration of 0.000002 mg/mL; then 5.0mL of the solution of (1) above was transferred to a 20mL headspace bottle and sealed.
Secondly, chromatographic conditions:
the column was a BD-1(30m 0.32mm 1.5 μm) gas chromatography column, mode constant pressure, pressure 11 psi. The sample injection mode is headspace sample injection, the sample injection port mode is split, the temperature of the sample injection port is 250 ℃, carrier gas used for sample analysis is high-purity nitrogen, the split ratio is 50:1, and the sample injection amount is 0.2 ml; the initial column temperature is 40 deg.C, maintained for 9min, and the temperature is raised at 20 deg.C per minute to 220 deg.C, and maintained for 3 min; the detector is an ECD detector, and the temperature of the detector is 300 ℃; the balance temperature of the headspace sample injector is 55 ℃, the temperature of the sampling needle is 85 ℃, the temperature of the transmission line is 95 ℃, the balance time is 35min, the CG cycle time is 31min, the pressurization time is 3min, the needle pulling time is 0.5min, and the carrier gas pressure is 20 psi.
Thirdly, experimental operation:
after the system is balanced, the solutions are taken and set according to the chromatographic conditions, and sample injection is carried out according to the following sequence: and (4) injecting a blank solution by 1-2 needles, injecting a detection limit solution by one needle, injecting a reference substance solution by 3 needles, and recording a chromatogram. Reporting the signal-to-noise ratio of the substance to be detected in the detection limit solution, and feeding the peak area and RSD value of the substance to be detected in the 3-needle reference solution.
TABLE 1 System suitability results
| Name (R) | Area of carbon tetrachloride |
| Blank space | |
| 0 | |
| Reference solution RS-1 | 5095.12 |
| Reference solution RS-2 | 5135.66 |
| Reference solution RS-3 | 5138.74 |
| RSD％ | 0.48 |
| Degree of separation | N/A |
| Detection limiting solution S/N | 38.6 |
The chromatogram is shown in fig. 1-2, which indicates that the white solution has no interference to the determination of the reference solution; the peak signal-to-noise ratio of the solvent to be detected in the detection limit solution is more than or equal to 3; RSD of the peak area of a continuous sample injection 3-needle reference substance solution (chromatogram is shown in figures 3-5) is less than or equal to 10.0 percent; in the first needle of contrast solution, the separation degree of the peak of the solvent to be detected and the nearest peak is more than or equal to 1.5, and the requirement is met. The system applicability meets the detection requirements.
Example 2 Attribute validation
Firstly, solution preparation:
see for the formulation of blank and control solutions: the formulation method of example 1;
test solution: taking 250mg of a sample, precisely weighing the sample into a 20mL headspace bottle, precisely weighing 5.0mL of DMF into the headspace bottle, sealing and shaking up; two parts are parallel;
adding a standard solution into a test sample: taking 250mg of a test article, precisely weighing the test article into a 20mL headspace bottle, precisely weighing 5.0mL of reference stock solution into the headspace bottle, sealing and shaking up.
Secondly, chromatographic conditions:
the same chromatographic conditions as in example 1 were used.
Thirdly, experimental operation:
on the premise of qualified system applicability, sample introduction is carried out according to the following sequence: sampling blank solution for 1 needle, reference solution for 1 needle, sample solution for sample for 1 needle, and sample solution for sample for standard solution for sample for 1 needle. Reporting a blank solution, a reference solution, a test sample adding standard solution, specific impurities, main peak retention time and peak area, and recording a chromatogram after completion.
TABLE 2 specificity results
The chromatogram is shown in fig. 6-8, which indicates that the blank solution has no interference to the solvent to be tested in the reference solution and the test solution; the minimum value of the separation degree of a solvent peak to be detected and adjacent chromatographic peaks in the test solution, the reference solution and the test sample added standard solution is more than or equal to 1.5; the retention time of the peak of the solvent to be detected in the test solution or the test and standard solution is consistent with that of the control solution, and the peak area of the solvent to be detected in the test and standard solution is increased compared with that of the test solution, which indicates that the specificity of the method is good.
Example 3 detection Limit verification
Firstly, solution preparation:
the preparation of the blank solution, the control solution and the detection limit solution is as follows: the formulation method in example 1.
Secondly, chromatographic conditions:
the same chromatographic conditions as in example 1 were used.
Thirdly, experimental operation:
on the premise of qualified system applicability, sample introduction is carried out according to the following sequence: taking the detection limit solution for continuous sample injection for 3 needles, and recording the chromatogram after completion. Reporting the detection limit solution signal-to-noise ratio; and calculating the percentage of the detection limit solution concentration corresponding to the concentration of the test sample solution.
TABLE 3 detection Limit results
The chromatogram is shown in FIGS. 9-11, and the signal-to-noise ratio is not less than 3 after the detection limit solution is continuously injected for 3 times, which meets the requirement; the minimum limit of carbon tetrachloride residue detection by the method can reach 0.04ppm concentration of 0.002 mug/mL, which is consistent with the detection limit of carbon tetrachloride being less than or equal to 4 ppm.
Example 4 determination of carbon tetrachloride solvent residue in linagliptin
Firstly, solution preparation:
diluent agent: n, N-dimethylformamide DMF;
blank solution: precisely measuring 5.0mL DMF to 20mL headspace bottles, sealing and shaking up;
control stock solutions: (1) taking 100mg of carbon tetrachloride, tightly weighing the carbon tetrachloride into a 100mL measuring flask, releasing the carbon tetrachloride to the scale with DMF, and shaking up; (2) precisely measuring 1.0mL of the solution (1) into a 50mL measuring flask, releasing to scale with DMF, and shaking up; precisely measuring 1.0mL of the solution (2) into a 100mL measuring flask, releasing to scale with DMF, and shaking up to obtain the final product;
control solution: precisely transferring 5.0mL of the control stock solution into a 20mL headspace bottle, capping, and sealing to obtain the final product;
detection limiting solution: (1) transferring 1mL of the control stock solution to a 100mL measuring flask, diluting the control stock solution to a scale mark with DMF, and shaking up; then 5.0mL of the solution (1) is transferred into a 20mL headspace bottle and sealed;
test solution: taking 250mg of a test product linagliptin, precisely weighing the test product linagliptin into a 20mL headspace bottle, precisely weighing 5.0mL of DMF into the headspace bottle, sealing and shaking up; in parallel, two portions were used.
Secondly, chromatographic conditions:
the column was a BD-1(30m 0.32mm 1.5 μm) capillary column, mode constant pressure, pressure 11 psi. The sample injection mode is headspace sample injection, the sample injection port mode is split, the temperature of the sample injection port is 250 ℃, carrier gas used for sample analysis is high-purity nitrogen, the split ratio is 50:1, and the sample injection amount is 0.2 ml; the initial column temperature is 40 deg.C, maintained for 9min, and the temperature is raised at 20 deg.C per minute to 220 deg.C, and maintained for 3 min; (ii) a The detector is an ECD detector, and the temperature of the detector is 300 ℃; the equilibrium temperature of the headspace sampler was 55 deg.C, the sample needle temperature was 85 deg.C, the transfer line temperature was 95 deg.C, the equilibration time was 35min, the CG cycle time was 31min, the pressurization time was 3min, the needle withdrawal time was 0.5min, and the carrier gas pressure was 20 psi.
The detection limit of carbon tetrachloride is less than or equal to 4 ppm.
Thirdly, experimental operation:
after the system is balanced, sample introduction is carried out according to the following sequence: taking blank solution for continuous sample injection, 1-2 needles for sample injection, 1 needle for sample injection of detection limit solution, 3 needles for continuous sample injection of reference solution, 1 needle for sample injection of 2 parts of test solution (batch one), 2 needles for sample injection of 2 parts of test solution (batch two), 1 needle for sample injection of reference solution (10-12 needles per interval) and 1 needle for sample injection of reference solution (end), and recording a chromatogram after completion.
Fourthly, judging according to the following steps:
the test result of the test article is judged as follows:
if the solvent carbon tetrachloride to be detected in the test sample is not detected or is detected, but is smaller than the peak area of the detection limit solution carbon tetrachloride, reporting the result: not detected;
if the peak area of the carbon tetrachloride solution to be detected in the test solution is larger than or equal to the peak area of the detection limit carbon tetrachloride and smaller than the average value of the carbon tetrachloride peak areas of the 3-needle reference solution, the result report is less than 4 ppm; and if the average value of the areas of the carbon tetrachloride peaks of 3 reference solutions is equal, reporting the result: 4 ppm;
if the peak area of the carbon tetrachloride solution to be detected in the test solution is larger than the average value of the carbon tetrachloride peak areas of the 3-needle reference solution, the result report is larger than 4 ppm.
Fifthly, detection results are as follows:
the content of each residual solvent in the test sample was calculated according to the formula, and the results are shown in table 4 below.
TABLE 4CCl4Solvent residue detection results
The chromatograms are shown in FIGS. 12-16, and the results show that: the results of the CCl4 solvent residues in the two batches of linagliptin are all undetected, which indicates that the carbon tetrachloride solvent to be detected in the test sample is smaller than the carbon tetrachloride peak area of the detection limit solution, so the result is output as undetected, and the requirement that the detection limit of the carbon tetrachloride is less than or equal to 4ppm is met.
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 (10)
1. A gas chromatography analysis method for carbon tetrachloride solvent residue in linagliptin is characterized in that N, N-dimethylformamide is used as a diluting solvent to prepare a reference solution and a test solution; and detecting and analyzing the residue of the carbon tetrachloride solvent in the sample by adopting a headspace sampling method and adopting gas chromatography.
2. The analytical method according to claim 1, wherein the gas chromatography detection uses a chromatographic column comprising: a BD-1 capillary column or other similar packed chromatographic column, said other similar packed chromatographic column being: HP-1, Ultra-1, SPB-1, CP-Sil 5CB Low Black/MS, Rtx-1, BP-1, OV-101, 007-1(MS), SP-2100, SE-30, CP-Sil 5CB MS, ZB-1, AT-1, MDN-1, or ZB-1.
3. The analytical method according to claim 2, wherein the initial column temperature in the gas chromatography is 30 to 50 ℃ for 5 to 15min, and the temperature is raised to 200 to 250 ℃ at a rate of 10 to 30 ℃ per minute for 1 to 10 min.
4. The analytical method according to claim 1, wherein the gas chromatography detector adopts an ECD detector, and the temperature of the detector is 200-400 ℃.
5. The analysis method according to claim 1, wherein the carrier gas in the gas chromatography detection is high-purity nitrogen, high-purity helium or high-purity hydrogen, and the split ratio is 5-50: 1.
6. The analytical method according to claim 1, wherein the sample injection volume in the gas chromatography detection is 0.1-1 ml.
7. The analytical method according to claim 1, wherein the sample inlet temperature in the gas chromatography detection is 100 to 300 ℃.
8. The analytical method according to claim 1, wherein the parameters of the headspace sampler in the gas chromatography assay are: the balance temperature is 50-100 ℃, the balance time is 20-40 min, the temperature of a sampling needle is 60-120 ℃, the temperature of a transmission line is 80-120 ℃, the GC cycle time is 30-60 min, the pressurization time is 1-10 min, the needle pulling time is 0.1-2 min, and the carrier gas pressure is 10-30 psi.
9. The analytical method according to claim 1, wherein the concentration of the sample solution is 1 to 100 mg/ml.
10. The assay of any one of claims 1 to 9, wherein the chromatographic conditions are as follows: the chromatographic column is a BD-1 gas chromatographic column, the mode is constant pressure, and the pressure is 11 psi; sample headspace sampling, wherein the sampling port mode is split flow, the sampling port temperature is 250 ℃, carrier gas used for sample analysis is high-purity nitrogen, the split flow ratio is 50:1, and the sampling amount is 0.2 ml; the initial column temperature is 40 deg.C, maintained for 9min, and the temperature is raised at 20 deg.C per minute to 220 deg.C, and maintained for 3 min; the detector is an ECD detector, and the temperature of the detector is 300 ℃; the balance temperature of the headspace sample injector is 55 ℃, the temperature of the sampling needle is 85 ℃, the temperature of the transmission line is 95 ℃, the balance time is 35min, the CG cycle time is 31min, the pressurization time is 3min, the needle pulling time is 0.5min, and the carrier gas pressure is 20 psi.
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