CN109668988B - Method for analyzing and determining 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate - Google Patents
Method for analyzing and determining 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate Download PDFInfo
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Abstract
The invention provides a method for analyzing and determining genotoxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate by using an HPLC method. The built high-efficiency liquid phase analysis method can accurately determine the potential genotoxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile in the trelagliptin succinate by adopting octadecylsilane chemically bonded silica as a stationary phase, a phosphoric acid aqueous solution and an acetonitrile solution as mobile phases and adopting a gradient elution mode. The HPLC-UV method is simple to operate, short in analysis time, high in accuracy and good in repeatability, the sensitivity can reach 1.6ppm, a reliable detection method is provided for the quality standard of trelagliptin succinate, a guarantee is provided for the healthy medication of patients, and the method belongs to the technical field of medicines.
Description
Technical Field
The invention particularly discloses a drug analysis method for determining a potential genotoxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate by using an HPLC (high performance liquid chromatography) method. Provides guarantee for the healthy medication of patients, and belongs to the technical field of medicines.
Background
Trelagliptin (Trelagliptin) is a once-weekly inhibitor of dipeptidyl peptidase IV (DPP-4) that controls blood glucose levels by selective, sustained inhibition of DPP-4. DPP-4 is an enzyme that triggers the inactivation of incretins (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)), and these 2 incretins play an important role in blood glucose regulation. Inhibiting DPP-4 can increase blood sugar level dependent insulin secretion, thereby controlling blood sugar level. For the medicine, the purity of the main component is a decisive factor of the medicine effect, so that the subsequent detection of the medicine in preparation is very important. Trelagliptin succinate with the chemical name 2- [ [6- [ (3R) -3-amino-1-piperidinyl]-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H) -pyrimidinyl]Methyl radical]-4-fluoro-benzonitrile succinate of formula: c18H20FN5O2·C4H6O4Is mainly used for treating type II diabetes patients, has the advantage of long half-life period, and is taken once a week. The structural formula is as follows:
the 2-bromomethyl-6-fluorobenzonitrile is an important starting material in the synthesis process of trelagliptin succinate, and the 2-bromomethyl-6-fluorobenzonitrile is easy to generate 2- (dibromomethyl) -4-fluorobenzonitrile in the synthesis process. The production process is as follows:
2- (dibromomethyl) -4-fluorobenzonitrile is a halogenated alkane structure, and compounds with such warning structures are defined as potential genotoxic impurities by ICH (International harmonization for registration of human drugs), FDA (food and drug administration in the United states) and EMEA (European drug evaluation agency), and therefore, the content of 2- (dibromomethyl) -4-fluorobenzonitrile needs to be controlled in trelagliptin succinate. ICH, guide to genetic toxicity testing and results analysis for human drugs, is recognized as an acceptable risk for most drugs by ingesting up to 1.5 μ g of genotoxic impurities per day. The maximum weekly intake of trelagliptin succinate is 100mg and the daily dosage is set to 100mg for strict control of genotoxic impurities, so that the corresponding limit of 2- (dibromomethyl) -4-fluorobenzonitrile is (1.5. mu.g/day)/(100 mg/day): 15 ppm.
In recent years, with the gradual soundness of relevant regulations of domestic and foreign medical administration departments, research on genotoxic impurities has become one of the keys for ensuring the product quality. At present, the USP, EP, JP, Chinese pharmacopoeia and related documents and patents have no report of toxic impurities of the trelagliptin succinate gene.
Disclosure of Invention
The invention provides a method for analyzing and determining potential genotoxic impurities, namely 2- (dibromomethyl) -4-fluorobenzonitrile, in trelagliptin succinate by using a high performance liquid chromatography.
The invention provides a method for analyzing and determining genotoxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate by using an HPLC method, which comprises the following steps:
(1) chromatographic conditions are as follows: using octadecylsilane chemically bonded silica as a stationary phase, using a phosphoric acid aqueous solution as a mobile phase A, using an acetonitrile solution as a mobile phase B, and performing gradient elution;
(2) preparation of sample solution: preparing a sample to be detected into a sample solution by using an acetonitrile aqueous solution as a solvent;
(3) separation and analysis: injecting the sample solution into a high performance liquid chromatograph to finish the determination of the toxic impurity of the trelagliptin perylate gene, wherein the toxic impurity of the gene is 2- (dibromomethyl) -4-fluorobenzonitrile.
In the above method of the present invention, the chromatographic column of the stationary phase octadecylsilane chemically bonded silica has a particle size of 3.5um, a length of 100mm, and an inner diameter of 4.6 mm.
In the above method of the present invention, the acetonitrile solution used as the solvent in the step (2) has an acetonitrile concentration of 20% to 80%, preferably 50%.
In the above method of the present invention, the concentration of phosphoric acid in the aqueous phosphoric acid solution as the mobile phase a is 0.05% to 0.15%. The phosphoric acid concentration is preferably 0.1%.
In the above method of the present invention, the flow rate of the mobile phase is 0.9 to 1.1ml/min, preferably 1.0 ml/min.
In the above method of the present invention, the column temperature of the column is 35 to 45 ℃, preferably 38 to 42 ℃, and more preferably 40 ℃.
In the above method of the present invention, the detection wavelength is 234 nm; the injection volume was 10. mu.l.
In the above method of the present invention, the elution gradient is:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 50 | 50 |
| 6.0 | 50 | 50 |
| 6.01 | 10 | 90 |
| 10.0 | 10 | 90 |
| 10.10 | 50 | 50 |
| 16.0 | 50 | 50 |
Through the structural analysis of impurities 2- (dibromomethyl) -4-fluorobenzonitrile and trelagliptin succinate, according to the conditions of acid-base difference and the like of a compound, octadecylsilane chemically bonded silica is selected as a stationary phase, and a phosphoric acid aqueous solution and acetonitrile are selected as mobile phases, so that the separation effect between the 2- (dibromomethyl) -4-fluorobenzonitrile and the trelagliptin succinate and adjacent unknown impurities is ensured; 2 isocratic elution gradient elution modes are adopted, wherein the first isocratic (the ratio of phosphoric acid aqueous solution to acetonitrile is 50:50) is used for separating 2- (dibromomethyl) -4-fluorobenzonitrile from the trelagliptin succinate and other unknown impurity baselines, and the second isocratic (the ratio of phosphoric acid aqueous solution to acetonitrile is 10:90) is used for eluting the low-polarity impurities in the trelagliptin succinate from the system so as to prevent the interference of the detection of the next sample; meanwhile, the 2- (dibromomethyl) -4-fluorobenzonitrile has no dissociating group and small polarity, the trelagliptin succinate has high polarity and is easily soluble in water, and a solution with the volume ratio of water to acetonitrile of 50:50 is used as a diluent (the proportion of an organic phase with the same first isocratic degree), so that the purpose of sample dissolution is achieved, the sample is prevented from generating a solvent effect, and the like, and the extraction recovery rate of the 2- (dibromomethyl) -4-fluorobenzonitrile is improved.
The method for analyzing and determining the genotoxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile in the trelagliptin perylate has the sensitivity of 1.6ppm, plays an important role in establishing and improving the quality standard of the trelagliptin perylate raw material medicine and the preparation, and provides a reference basis for researching the genotoxic impurity of other medicines adopting similar initial raw materials and synthetic routes.
Drawings
Figure 1 localization solution diagram of trelagliptin succinate in example 1;
FIG. 2 is a scheme of a positioning solution of 2- (dibromomethyl) -4-fluorobenzonitrile in example 1;
FIG. 3 is a scheme of a solution for locating 2-bromomethyl-6-fluorobenzonitrile in example 1;
FIG. 4 is an enlarged view of a part of a white solvent in example 1;
FIG. 5 is an enlarged view of a portion of the proprietary solution of example 1;
FIG. 6 is an enlarged view of a part of a detection limiting solution in example 2;
FIG. 7 is a partial enlarged view of the quantitative limiting solution in example 2;
FIG. 8 is an enlarged view of a portion of the linear solution of example 3;
FIG. 9 Linear working diagram of 2- (dibromomethyl) -4-fluorobenzonitrile in example 3.
Detailed Description
The invention is further illustrated by the following specific examples. It should be understood that: the examples of the present invention are provided for illustration only and not for limitation of the present invention. The technical scheme obtained by simply improving the invention or equivalently replacing the conventional means or components on the basis of the technical scheme of the invention belongs to the protection scope of the invention.
Example A specificity and impurity localization test
(1) Preparation of sample solution
Solvent: 50% aqueous acetonitrile solution
Positioning solution: appropriate amounts of trelagliptin succinate, 2- (dibromomethyl) -4-fluorobenzonitrile and 2-bromomethyl-6-fluorobenzonitrile are precisely weighed, and are respectively placed in different measuring bottles, and are dissolved and diluted by adding a solvent (50% acetonitrile aqueous solution) to prepare solutions containing 6.67mg/ml, 1mg/ml and 1ug/ml of trelagliptin succinate, 2- (dibromomethyl) -4-fluorobenzonitrile and 2-bromomethyl-6-fluorobenzonitrile respectively as compound positioning solutions.
A special solution: 10mg of 2- (dibromomethyl) -4-fluorobenzonitrile is precisely weighed, placed in a 10ml measuring flask, dissolved and diluted to 10ml mark by adding a solvent (50% acetonitrile water solution), and shaken up. Taking 100ul of the solution in a 100ml volumetric flask, uniformly mixing the solution with a diluent, and performing constant volume to obtain a 2- (dibromomethyl) -4-fluorobenzonitrile stock solution; taking 66.67mg of trelagliptin succinate, precisely weighing the trelagliptin succinate, placing the trelagliptin succinate into a 10ml measuring flask, precisely weighing 1ml of 2- (dibromomethyl) -4-fluorobenzonitrile stock solution into the measuring flask, adding a solvent (50% acetonitrile aqueous solution) to dissolve the trelagliptin succinate, diluting the solution to a scale of 10ml, shaking the solution uniformly, and preparing a solution containing 6.667mg/ml of trelagliptin succinate and 1 mu g/ml of 2- (dibromomethyl) -4-fluorobenzonitrile as a special solution.
Precisely measuring 10 mul of each of the blank solvent, the positioning solution and the special solution, respectively injecting the blank solvent, the positioning solution and the special solution into a liquid chromatograph, and detecting the chromatographic conditions according to the embodiment of the invention.
(2) Chromatographic conditions are as follows:
high performance liquid chromatograph: agilent 1100 was equipped with an ultraviolet detector.
A chromatographic column: agilent Zorbax Eclipse Plus C184.6mm. times.100 mm, 3.5 μm
Mobile phase A: 0.1% phosphoric acid aqueous solution: accurately transferring 1ml of phosphoric acid into 1L of water, mixing uniformly, and ultrasonically degassing.
Mobile phase B: acetonitrile
Gradient elution procedure:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0.0 | 50 | 50 |
| 6.0 | 50 | 50 |
| 6.01 | 10 | 90 |
| 10.0 | 10 | 90 |
| 10.10 | 50 | 50 |
| 16.0 | 50 | 50 |
Column temperature: 40 ℃; detection wavelength: 234 nm; flow rate: 1.0 ml/min; sample introduction volume: 10 μ l
(3) Results of the experiment
And (3) positioning test results: the retention time of trelagliptin succinate, 2- (dibromomethyl) -4-fluorobenzonitrile and 2-bromomethyl-6-fluorobenzonitrile is respectively 0.786min, 4.991min and 3.243min, and the spectra are shown in attached figures 1-3.
Results of the specificity test: the blank solvent does not interfere with the detection of 2- (dibromomethyl) -4-fluorobenzonitrile; in the special solution, the degrees of separation of 2- (dibromomethyl) -4-fluorobenzonitrile and adjacent unknown impurity peaks are all more than 1.5; and the chromatographic peak purity angles of the impurity I and the impurity II are both smaller than the purity threshold value, which indicates that the chromatographic peak is a single component. The above shows that the method specificity meets the requirements. The results are shown in Table 1, and the spectra are shown in figure 4 and figure 5.
TABLE 1 method specificity test results
Example two detection and quantitation limits
(1) Preparation of sample solution
Solvent: 50% aqueous acetonitrile solution
Determination of baseline noise: precisely measuring 10 mu l of solvent, injecting the solvent into a liquid chromatograph, continuously injecting a sample of 3 needles, and detecting the chromatographic condition according to the embodiment of the invention. The blank baseline noise was recorded over the time range of peak appearance for 2- (dibromomethyl) -4-fluorobenzonitrile and the average was calculated.
Preparation of a quantitative limiting solution: taking appropriate amount of each hetero 2- (dibromomethyl) -4-fluorobenzonitrile, precisely weighing, dissolving with a solvent, gradually diluting, detecting according to the chromatographic condition of the embodiment of the invention until the peak height of the hetero 2- (dibromomethyl) -4-fluorobenzonitrile is diluted to a value (namely, signal-to-noise ratio, S/N) of about 10 of the ratio of the corresponding noise to the peak height of the hetero 2- (dibromomethyl) -4-fluorobenzonitrile, wherein the ratio of the sample concentration to the measured concentration of the sample is the quantitative limit, continuously injecting samples with the concentration for 3 needles, and calculating the average value of the peak heights.
Preparation of detection limiting solution: taking appropriate amount of each hetero 2- (dibromomethyl) -4-fluorobenzonitrile, precisely weighing, dissolving by using a solvent, gradually diluting, detecting according to the chromatographic condition of the embodiment of the invention until the peak height of the hetero 2- (dibromomethyl) -4-fluorobenzonitrile is diluted to a value (namely, signal-to-noise ratio, S/N) of about 3 of the ratio of the corresponding noise to the peak height of the hetero 2- (dibromomethyl) -4-fluorobenzonitrile, wherein the ratio of the sample concentration to the measured concentration of the sample is the detection limit, and injecting 1 needle by using the concentration.
(2) Chromatographic conditions
The chromatographic conditions were the same as in example 1
(3) Results of the experiment
Test results show that the detection limit and the quantitative limit of the 2- (dibromomethyl) -4-fluorobenzonitrile are 0.5ppm and 1.5ppm under the analysis method, namely the 2- (dibromomethyl) -4-fluorobenzonitrile with the content of more than 1.6ppm in a sample can be detected and accurately quantified. Thus, the sensitivity of the method is satisfactory. The results of detection limit and quantitation limit are shown in Table 2, and the detection limit and quantitation limit solution maps are shown in FIGS. 6 and 7.
TABLE 2 detection limit and quantitation limit results
Example trilinear
(1) Preparation of sample solution
Accurately weighing 10mg of 2- (dibromomethyl) -4-fluorobenzonitrile respectively, placing the weighed materials into a 100ml measuring flask, adding a solvent to dissolve and dilute the materials to a scale, and shaking up; precisely measuring 1ml, placing in a 100ml measuring flask, adding solvent to dilute to scale, and shaking up to obtain linear stock solution.
Precisely measuring linear stock solutions 0.5ml, 1.5ml, 2.5ml, 4.0ml, 5.0ml, 6.0ml and 7.5ml, respectively placing in different 50ml measuring bottles, adding a solvent to dilute to a scale, and shaking up to be respectively used as 10%, 30%, 50%, 80%, 100%, 120% and 150% linear solutions of limits. According to the chromatographic condition detection, a linear equation and a correlation coefficient are calculated.
(2) Chromatographic conditions
The chromatographic conditions were the same as in example 1
(3) Results of the experiment
Test results show that the correlation coefficient of a linear equation is more than 0.999 and the linear relation meets the requirements when the 2- (dibromomethyl) -4-fluorobenzonitrile is in a concentration range of 150 percent with the limit of quantification. The test results are shown in Table 3, and the linear solution typical pattern is shown in FIG. 8, and the working curve pattern is shown in FIG. 9.
TABLE 32- (dibromomethyl) -4-fluorobenzonitrile Linear test results
Example four accuracies
(1) Preparation of sample solution
Control stock solutions: accurately weighing 10mg of 2- (dibromomethyl) -4-fluorobenzonitrile respectively, placing the weighed materials into a 100ml measuring flask, adding a solvent to dissolve and dilute the materials to a scale, and shaking up; precisely measuring 1ml, placing in a 100ml measuring flask, adding solvent to dilute to scale, and shaking up to obtain linear stock solution.
Control solution: 1.0ml of the control stock solution was taken in a 10ml volumetric flask and the volume was determined by using the diluent to prepare a solution having a 2- (dibromomethyl) -4-fluorobenzonitrile concentration of 0.1. mu.g/ml.
Accuracy solution: taking 66.67mg of a sample, 2 parts in total, precisely weighing, respectively placing in 10ml measuring flasks, adding a solvent for dissolving, diluting to a scale, and shaking up to obtain a blank solution; and taking 66.67mg of test sample, 9 parts in total, taking 3 parts in each group, 3 groups in total, respectively placing the test sample in 10ml measuring bottles, respectively adding 0.8ml, 1.0ml and 1.2ml of reference substance stock solution into each group, then adding a solvent for dissolving and diluting to a scale, shaking up, and respectively using the test sample as the accuracy test solutions of 80%, 100% and 120% of the limit. The above solutions were tested according to the chromatographic conditions described in the present invention.
(2) Chromatographic conditions
The chromatographic conditions were the same as in example 1
(3) Results of the experiment
And calculating the detected amount of the 2- (dibromomethyl) -4-fluorobenzonitrile in each group of samples, deducting the data of the content of the 2- (dibromomethyl) -4-fluorobenzonitrile in the samples to obtain an actual detected amount, calculating the ratio of the actual detected amount to the theoretical added amount, taking the result as recovery rate data, and counting the range, the average value and the Relative Standard Deviation (RSD) of the recovery rate for evaluating the accuracy of the method. Test results show that the recovery rate of the solution for accurately measuring the content of the 2- (dibromomethyl) -4-fluorobenzonitrile is 100.2-109.4%, the RSD is less than 5.0%, and the accuracy of the method is good. The test results are shown in Table 5
TABLE 5 accuracy results
Example five durability
(1) Preparation of sample solution
Test solution: same as example 4 (sample solution and sample plus limit 100% level solution)
(2) Chromatographic conditions
The sample solution was examined and the recovery of 2- (dibromomethyl) -4-fluorobenzonitrile under each condition was recorded while keeping the other parameters in conformity with the chromatographic conditions in example 1, with the flow rates set to 0.9ml/min and 1.1ml/min, the column temperature set to 38 ℃ and 42 ℃ and the wavelengths set to 232nm and 236nm, respectively, and the initial ratio of mobile phase B was 48% and 52%. The test results are shown in Table 6
TABLE 6 durability results
In conclusion, the method provided by the invention is simple to operate, high in sensitivity and good in specificity, can accurately determine the potential genotoxic impurities in the trelagliptin succinate, and is a prospective method for improving and innovating the processes of the raw material medicines and the preparation of the trelagliptin succinate and further improving the quality standard.
Claims (6)
1. A method for analyzing and determining 2- (dibromomethyl) -4-fluorobenzonitrile in trelagliptin succinate is characterized in that,
(1) chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a stationary phase, phosphoric acid aqueous solution with the concentration of 0.05-0.15% is used as a mobile phase A, acetonitrile solution is used as a mobile phase B, and gradient elution is carried out;
the elution gradient was:
The flow rate of the mobile phase is 0.9-1.1 ml/min; the temperature of the chromatographic column is 38-42 ℃;
(2) preparing a sample solution: preparing a sample to be detected into a sample solution by using an acetonitrile aqueous solution with the concentration of 20-90% as a solvent;
(3) separation and analysis: injecting the sample solution into a high performance liquid chromatograph, and detecting the wavelength to be 234nm to finish the determination of the toxic impurity 2- (dibromomethyl) -4-fluorobenzonitrile and 2-bromomethyl-6-fluorobenzonitrile of the trelagliptin succinate gene.
2. The method of claim 1, wherein the stationary phase octadecylsilane bonded silica chromatography column has a particle size of 3.5 μm, a length of 100mm, and an inner diameter of 4.6 mm.
3. The process according to claim 1, wherein the concentration of acetonitrile in the aqueous acetonitrile solution used as the solvent in the step (2) is 50%.
4. The method according to claim 1, wherein the concentration of phosphoric acid in the aqueous phosphoric acid solution as the mobile phase A is 0.1%.
5. The method of claim 1, wherein the flow rate of the mobile phase is 1.0 ml/min; the column temperature of the chromatographic column was 40 ℃.
6. The method of claim 1, wherein the injection volume is 10 μ l.
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| CN109668988A (en) | 2019-04-23 |
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