CN114113362B - Method for determining impurity content of intermediate of linagliptin bulk drug - Google Patents
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Abstract
The invention belongs to the technical field of medicine analysis, and particularly relates to a method for determining the content of linagliptin impurity 110 in linagliptin bulk drug. The method establishes a high performance liquid chromatography analysis system aiming at the impurity 110 in the linagliptin bulk drug, and realizes the content measurement of the intermediate impurity 110 of the linagliptin bulk drug, thereby effectively controlling the quality of the linagliptin bulk drug. The method is simple, quick, accurate and good in specificity, and has good application value in quality detection and control of the linagliptin bulk drug.
Description
Technical Field
The invention belongs to the technical field of medicine analysis. More particularly, relates to a method for determining the content of linagliptin impurity 110 which is an intermediate of linagliptin raw material medicines.
Background
Linagliptin (Linagliptin) is an inhibitor of dipeptidyl peptidase-4 (DPP-4) and is an effective drug for treating type II diabetes, however, impurities such as starting materials, intermediates and the like can be introduced into the Linagliptin drug substance during the production process, so that the quality and the curative effect of the Linagliptin drug substance are affected, such as impurity Linagliptin impurity 110 (CAS number: 2638512-67-9).
How to accurately measure the content of impurities in the linagliptin bulk drug, so as to effectively control the quality of linagliptin products, becomes a critical problem to be solved urgently, but the prior art has few choices of methods for detecting impurities in the linagliptin bulk drug, and even has no detection method for intermediate impurities linagliptin impurities 110.
For example, chinese patent application CN 107870209A discloses a method for determining impurity content in linagliptin bulk drug, the detected impurity isIntermediate impurity linagliptin impurity 110 cannot be detected.
Disclosure of Invention
The invention aims to solve the technical problem that no method for measuring the linagliptin impurity 110 in the linagliptin bulk drug exists in the prior art, and provides a simple, quick and accurate method for measuring the impurity content.
The above object of the present invention is achieved by the following technical solutions:
the method for determining the impurity content of the intermediate of the linagliptin bulk drug comprises the steps of analyzing the linagliptin bulk drug by a high performance liquid chromatography analysis method to obtain a chromatogram so as to determine the impurity content of the intermediate of the linagliptin bulk drug, wherein the intermediate impurity is linagliptin impurity 110, and the structural formula is as follows:
preferably, the chromatographic conditions of the high performance liquid chromatography method are:
detection wavelength: 225-235 nm of the particle size of the nano-particles,
column temperature: 25-30 ℃,
mobile phase: methanol-water, the water-water ratio,
flow rate: 1.0 to 2.0ml/min,
sample injection amount: 20 to 30 mu L of the total weight of the mixture,
elution procedure: the elution is carried out by equal flow and degree,
run time: 20-30 min.
Preferably, the chromatographic column of the high performance liquid chromatography method isInertsl @ ODS-3, 4.6X1250 mm,5 μm, or a packed column.
Preferably, the detector of the high performance liquid chromatography method is VWD.
Preferably, the blank solution/diluent of the high performance liquid chromatography method is acetonitrile.
Preferably, the volume ratio of the mobile phase methanol to water is (3-5): 1.
More preferably, the mobile phase methanol-water volume ratio is 4:1.
Preferably, the linagliptin drug substance is provided in the form of a test solution.
Preferably, the solvent of the test solution is acetonitrile.
Preferably, the method comprises the following steps:
s1, setting chromatographic conditions
Chromatographic column: inertsl @ ODS-3，4.6×250mm，5μm，
A detector: VWD is used to determine the position of the VWD,
detection wavelength: 225-235 nm of the particle size of the nano-particles,
column temperature: 25-30 ℃,
mobile phase: methanol-water, the water-water ratio,
flow rate: 1.0 to 2.0ml/min,
sample injection amount: 20 to 30 mu L of the total weight of the mixture,
elution procedure: the elution is carried out by equal flow and degree,
run time: 20-30 min;
s2, preparing a solution
Blank solution: acetonitrile;
control stock solution: 0.01mg/ml of linagliptin impurity 110 solution as a reference substance, and methanol as a solvent;
control solution: diluting the reference stock solution with acetonitrile to 0.03mg/ml to obtain the final product;
detection limit solution: diluting the reference stock solution with acetonitrile to 0.003mg/ml to obtain the final product;
test solution: 1mg/ml of linagliptin raw material medicine solution, wherein the solvent is acetonitrile;
s3, sequentially injecting the solutions into a chromatograph, recording a chromatogram, and analyzing a detection result according to the chromatogram.
In addition, in the most preferred embodiment, in the method for determining the impurity content of the intermediate of the linagliptin bulk drug, the chromatographic conditions of the high performance liquid chromatography method are as follows:
chromatographic column: inertsl @ ODS-3,4.6X 250mm,5 μm or similar packed chromatography column,
a detector: VWD is used to determine the position of the VWD,
the detection wavelength is 230nm, and the detection time is as long as the detection time is,
column temperature: 30 ℃,
mobile phase: methanol-water, the water-water ratio,
flow rate: 1.0ml/min of the total volume of the mixture,
sample injection amount; 30. Mu.L of the solution,
elution procedure: the elution is carried out by equal flow and degree,
run time: 30min;
preferably, the method for judging the analysis and detection result is as follows:
a is the average value of the peak areas of linagliptin impurities 110 in the reference substance solution;
b is the peak area of the linagliptin impurity 110 in the detection limit solution;
if the average value of the peak areas of the linagliptin impurities 110 in the sample solution is larger than A, reporting that the average value is larger than 300ppm, namely the content of the linagliptin impurities 110 in the sample solution is larger than 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the test sample solution is equal to A, reporting 300ppm, namely representing that the content of the linagliptin impurities 110 in the test sample solution is 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the sample solution is smaller than A and larger than or equal to B, reporting that the average value is smaller than 300ppm, namely the content of the linagliptin impurities 110 in the sample solution is smaller than 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the test solution is smaller than B, the detection is reported to be undetected, namely the linagliptin impurities 110 in the test solution are not contained.
The invention has the following beneficial effects:
the invention provides a brand-new detection method for detecting the linagliptin impurity 110 which is an intermediate of linagliptin bulk drug, and the content of the impurity in the linagliptin bulk drug can be simply, rapidly and accurately measured, so that the quality of the linagliptin bulk drug is effectively controlled.
Drawings
Fig. 1 is an HPLC profile of the blank solutions of example 1 and example 2.
FIG. 2 is an HPLC chart of the detection limit solution of example 1.
FIG. 3 is an HPLC chart of control solution 1 of example 1.
FIG. 4 is an HPLC chromatogram of control solution 2 of example 1.
FIG. 5 is an HPLC chromatogram of control solution 3 of example 1.
FIG. 6 is an HPLC chart of sample solution 1 of example 1.
FIG. 7 is an HPLC chart of sample solution 2 of example 1.
FIG. 8 is an HPLC chromatogram of the detection limit solution of example 2.
FIG. 9 is an HPLC chart of control solution 1 of example 2.
FIG. 10 is an HPLC chart of comparative sample solution 2 of example 2.
FIG. 11 is an HPLC chromatogram of control solution 3 of example 2.
FIG. 12 is an HPLC plot of a blank solution of example 3.
FIG. 13 is an HPLC chromatogram of the detection limit solution of example 3.
FIG. 14 is an HPLC chromatogram of control solution 1 of example 3.
FIG. 15 is an HPLC chromatogram of control solution 2 of example 3.
FIG. 16 is an HPLC chromatogram of control solution 3 of example 3.
FIG. 17 is an HPLC chart of sample solution 1 of example 3.
FIG. 18 is an HPLC chromatogram of sample addition solution 1 of example 3.
FIG. 19 is an HPLC chromatogram of sample addition solution 2 of example 3.
FIG. 20 is an HPLC chromatogram of sample addition solution 3 of example 3.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 linagliptin intermediate impurity linagliptin impurity 110 content determination
1. Detecting a sample
Linagliptin impurity 110 control: purchased from Jiangsu Huiyuan pharmaceutical Co., ltd (CAS number: 2638512-67-9).
Linagliptin bulk drug: purchased from the milk source east yang photopharmaceuticals company.
2. Detection method
S1, setting chromatographic conditions according to Table 1
TABLE 1 chromatographic data parameters
S2, preparing a solution
Blank solution: taking a proper amount of acetonitrile into a liquid phase vial to obtain the catalyst;
control stock solution: weighing the linagliptin impurity 110 reference substance 25mg to 25ml measuring flask, adding a proper amount of methanol, dissolving by ultrasonic, diluting to scale with methanol, shaking uniformly to obtain reference substance mother liquor, transferring 1.0ml reference substance mother liquor to 100ml measuring flask, diluting with acetonitrile, fixing volume, and shaking uniformly to obtain the final product;
control solution: transferring 3.0ml of reference stock solution into a 100ml measuring flask, diluting with acetonitrile, fixing volume, and shaking;
detection limit solution: transferring 0.3ml of reference stock solution into a 100ml measuring flask, diluting with acetonitrile, fixing volume, and shaking;
test solution: preparing the linagliptin bulk drug into acetonitrile solution of 1mg/ml by using a 25ml volumetric flask, namely preparing 2 parts in parallel, namely a test solution 1 and a test solution 2 respectively;
s3, sequentially injecting the solutions into a chromatograph, wherein the sample injection amount is shown in table 2, and recording the chromatogram.
TABLE 2 sample introduction amount of corresponding solutions
3. Detection result
The blank solution has an obvious peak at about 5.5 (figure 1), and the detection limit solution has a new peak at about 11.1 compared with the blank solution, and the peak area is 25.85 (figure 2); the peak time of the reference substance solutions 1 to 3 is the same as that of the detection limit solution, new peaks appear at about 11.1, the peak area of the reference substance solution 1 is 91.33 (figure 3), the reference substance solution 2 is 91.07 (figure 4), the reference substance solution 3 is 91.20 (figure 5), and the peak area average value of the reference substance solutions 1 to 3 is 91.20; the data of the results of the detailed content detection of the sample solutions 1 and 2, in which no new peak appears at about 11.1 (fig. 6 to 7), are shown in table 3:
TABLE 3 results of detection of linagliptin impurity 110 content
Judgment basis:
a is the average value of the peak areas of linagliptin impurity 110 in 3 consecutive control solutions, i.e. 91.20.
B is the area of the peak of the linagliptin impurity 110 in the detection limit solution, namely 25.85.
If the average value of the peak areas of the linagliptin impurities 110 in the test solution is greater than A, the report is greater than 300ppm, namely the content of the linagliptin impurities 110 in the test solution is represented to be greater than 300ppm.
If the average value of the peak areas of the linagliptin impurities 110 in the test solution is equal to A, 300ppm is reported, which represents that the content of the linagliptin impurities 110 in the test solution is 300ppm.
If the average value of the peak areas of the linagliptin impurities 110 in the test solution is less than a and greater than or equal to B, then less than 300ppm is reported, which is indicative of a content of the linagliptin impurities 110 in the test solution of less than 300ppm.
If the average value of the peak areas of the linagliptin impurities 110 in the test solution is smaller than B, the detection is not reported, namely that the test solution does not contain the linagliptin impurities 110.
As can be seen from table 3, the content of the intermediate impurity linagliptin impurity 110 of the linagliptin bulk drug detected in the present experiment is 0.
Example 2 test of the applicability of the method for detecting linagliptin intermediate impurity, linagliptin impurity 110
Steps S1, S2 are the same as in example 1;
s3, taking the solutions according to chromatographic conditions in the method description after the baseline is balanced, feeding 1-2 needles for blank solution, feeding 1 needle for detection limit solution, continuously feeding 3 needles for reference solution, and recording a chromatogram. The report blank solution diagram is shown in fig. 1, which shows that the impurity detection is not interfered, the signal to noise ratio (S/N) of the substance to be detected in the detection limit solution is 11.7, the capability of the solution to detect the impurity is shown in fig. 8, the peak areas of the substance to be detected in the reference solutions 1 to 3 are 92.77 (fig. 9), 93.46 (fig. 10) and 93.61 (fig. 11), respectively, and the Relative Standard Deviation (RSD) value is 0.49. The detailed data are shown in table 4:
TABLE 4 results of applicability of the method for detecting linagliptin impurity 110
As shown in Table 4, the signal to noise ratio of the detection limit solution is 11.7 and is more than 3, which indicates that the sensitivity of the detection method meets the detection requirement; the reference substance solution has a main peak area RSD of 0.49 and less than 15%, and meets the standard.
Example 3 specific and detection Limit verification of linagliptin impurity 110 detection method
S1 is the same as in example 1;
s2, preparing a sample adding standard solution, wherein the preparation method comprises the following steps: weighing the linagliptin bulk drug in a 20 mg-20 ml measuring flask, adding a 0.6m reference substance stock solution, adding a proper amount of acetonitrile, performing ultrasonic dissolution, diluting to a scale with acetonitrile, and shaking uniformly to obtain a 100% sample adding standard solution; preparing 3 parts in parallel;
s3, taking corresponding solutions to sample according to sample injection amounts of the table 5 on the basis of qualified system applicability, and recording corresponding chromatograms. Reporting the retention time, peak area and separation degree of each substance to be tested and adjacent peaks in the reference substance solution, the test substance solution and the test substance labeling solution.
TABLE 5 sample introduction amount of corresponding solutions
| Solution name | Number of sample injection needles |
| Blank solution | 1-2 needles |
| Detection limiting solution | 1 needle |
| Reference substance solution | 3 needles |
| Sample solution 1 | 1 needle |
| Test sample adding standard solution 1 | 1 needle |
| Sample adding standard solution 2 | 1 needle |
| Sample adding standard solution 3 | 1 needle |
The blank solution pattern is shown in fig. 12, which shows that the detection of impurities is not interfered, the detection limit solution is shown in fig. 13, which shows that the solution can detect the capability of impurities, the retention time of the control solution 1 is 11.141, the peak area is 92.77, the separation from adjacent peaks is complete (fig. 14), the retention time of the control solution 2 is 11.145, the peak area is 93.46, the separation from adjacent peaks is complete (fig. 15), the retention time of the control solution 3 is 11.147, the peak area is 93.61, the separation from adjacent peaks is complete (fig. 16), the retention time of the sample solution 1 is 11.280, the peak area is 57.07, the separation from adjacent peaks is 1.46 (fig. 17), the retention time of the sample labeling solution 1 is 11.172, the peak area is 146.68, the separation from adjacent peaks is 1.87 (fig. 18), the retention time of the sample labeling solution 2 is 11.172, the peak area is 146.02, the separation from adjacent peaks is 1.94 (fig. 19), the retention time of the sample labeling solution 3 is 11.173, the peak area is 148.35, the separation from adjacent peaks is 1.85, the detailed detection result is shown in fig. 20.85).
TABLE 6 specificity and detection Limit results
The ratio (R) of the peak area of the substance to be detected in the sample addition standard solution to the average value of the peak area of the substance to be detected in the reference solution is calculated according to the following formula:
wherein: AT+S is the peak area of the substance to be detected in the sample labeling solution;
AT is the peak area of the substance to be detected in the sample solution;
AS is the average value of the peak areas of substances to be detected in the 3-needle reference substance solution;
WT is the sample weighing amount (mg) of the sample in the sample solution;
WT+S is the sample weight (mg) of the sample in the sample addition solution.
As shown in Table 6, the separation degree of the 3-needle sample adding standard solution is greater than 1.0, which indicates that the separation capacity of the detection method meets the detection requirement; the blank solution has no interference to the substances to be detected in the sample solution and the reference substance solution; the retention time of the substances to be detected in the sample solution and the sample labeling solution is consistent with that of the reference substance solution, and compared with the sample solution, the peak area of the substances to be detected in the sample labeling solution is obviously increased, and the specific requirements are met.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (4)
1. A method for determining the impurity content of an intermediate of a linagliptin bulk drug is characterized in that the linagliptin bulk drug is analyzed by a high performance liquid chromatography analysis method to obtain a chromatogram so as to determine the impurity content of the intermediate of the linagliptin bulk drug,the intermediate impurity is linagliptin impurity 110, and the structural formula is:；
the chromatographic conditions of the high performance liquid chromatography method are as follows:
detection wavelength: 225-235 nm of the silicon dioxide,
column temperature: 30. at the temperature of the mixture,
mobile phase: methanol-water, volume ratio of 4:1,
flow rate: 1.0 The volume of the solution is ml/min,
sample injection amount: 20 to 30 mu L of the liquid crystal display device,
elution procedure: the elution is carried out by equal flow and degree,
run time: 20-30 min;
the chromatographic column of the high performance liquid chromatography is Inertsl @ ODS-3、4.6×250mm、5μm；
The blank solution/diluent of the high performance liquid chromatography method is acetonitrile;
the linagliptin bulk drug is provided in the form of a test solution, and the solvent of the test solution is acetonitrile.
2. The method of claim 1, wherein the detector of high performance liquid chromatography is VWD.
3. The method according to claim 1 or 2, comprising the steps of:
s1, setting chromatographic conditions:
chromatographic column: inertsl @ ODS-3，4.6×250mm，5μm，
A detector: VWD is used to determine the position of the VWD,
detection wavelength: 225-235 nm of the silicon dioxide,
column temperature: 30. at the temperature of the mixture,
mobile phase: methanol-water, volume ratio of 4:1,
flow rate: 1.0 The volume of the solution is ml/min,
sample injection amount: 20 to 30 mu L of the liquid crystal display device,
elution procedure: the elution is carried out by equal flow and degree,
run time: 20-30 min;
s2. Preparation of solution
Blank solution: acetonitrile;
control stock solution: 0.01mg/ml of linagliptin impurity 110 solution as a reference substance, and methanol as a solvent;
control solution: diluting the reference stock solution with acetonitrile to 0.03mg/ml to obtain the final product;
detection limit solution: diluting the reference stock solution with acetonitrile to 0.003mg/ml to obtain the final product;
test solution: 1mg/ml of linagliptin raw material medicine solution, wherein the solvent is acetonitrile;
and S3, sequentially injecting the solutions into a chromatograph, recording a chromatogram, and analyzing a detection result according to the chromatogram.
4. A method according to claim 3, wherein the analytical test results are determined by:
a is the average value of the peak areas of linagliptin impurities 110 in the reference substance solution;
b is the peak area of the linagliptin impurity 110 in the detection limit solution;
if the average value of the peak areas of the linagliptin impurities 110 in the sample solution is larger than A, reporting that the average value is larger than 300ppm, namely the content of the linagliptin impurities 110 in the sample solution is larger than 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the test sample solution is equal to A, reporting 300ppm, namely representing that the content of the linagliptin impurities 110 in the test sample solution is 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the sample solution is smaller than A and larger than or equal to B, reporting that the average value is smaller than 300ppm, namely the content of the linagliptin impurities 110 in the sample solution is smaller than 300ppm;
if the average value of the peak areas of the linagliptin impurities 110 in the test solution is smaller than B, the detection is reported to be undetected, namely the linagliptin impurities 110 in the test solution are not contained.
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| CN107870209A (en) * | 2016-09-28 | 2018-04-03 | 广东东阳光药业有限公司 | The method for determining impurity content in Li Gelieting bulk drugs |
| CN112592320A (en) * | 2020-12-22 | 2021-04-02 | 江苏慧聚药业有限公司 | Related substance of linagliptin intermediate and synthesis method thereof |
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