CN109975448B - Method for detecting related substances or/and content of dabigatran etexilate mesylate or preparation thereof - Google Patents
Method for detecting related substances or/and content of dabigatran etexilate mesylate or preparation thereof Download PDFInfo
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- CN109975448B CN109975448B CN201711465139.3A CN201711465139A CN109975448B CN 109975448 B CN109975448 B CN 109975448B CN 201711465139 A CN201711465139 A CN 201711465139A CN 109975448 B CN109975448 B CN 109975448B
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Abstract
A method for detecting related substances or/and content of dabigatran etexilate mesylate or a preparation thereof adopts high performance liquid chromatography for detection, and detection conditions comprise: a chromatographic column: reversed phase silica gel chromatographic column, detection wavelength: 210-400 nm, mobile phase: mobile phase A: a water phase containing a buffer solution, wherein the pH value is 4.25-4.40; the mobile phase B mainly comprises methanol or acetonitrile; the mobile phase is eluted by a gradient elution method. The detection method can separate chromatographic peaks of related substances of the dabigatran etexilate mesylate and the preparation thereof, and has good chromatographic peak separation degree.
Description
Technical Field
The invention relates to the field of related substance detection methods, in particular to a method for detecting related substances or/and contents of dabigatran etexilate mesylate or a preparation thereof.
Background
The dabigatran etexilate mesylate is developed by the German Boringer Yiger John company, is approved by the U.S. food and drug administration for stroke and systemic embolism prevention of patients with non-valvular atrial fibrillation in 2010, is a direct thrombin inhibitor, is a prodrug of dabigatran, belongs to a non-peptide thrombin inhibitor, releases the latter in vivo after oral administration, binds with fibrin specific sites of thrombin, prevents fibrinogen from being cracked into fibrin, thereby blocking the final step of a blood coagulation waterfall network and thrombus formation, is on the market, is an important development in the field of anticoagulant therapy and the field of potentially lethal thrombus prevention, and has milestone significance.
The related substances are mainly starting materials, intermediates, polymers, side reaction products brought in during the production process, degradation products in the storage process and the like. Related substance research is one of key projects in medicine quality research, and the content of the related substance not only reflects a direct index of medicine purity, but also has important safety significance.
Disclosure of Invention
The existing detection method for dabigatran etexilate mesylate or related substances of a preparation thereof is found in the application process, the existing method can only detect degradation impurities of capsules, and can not detect process impurities brought in the synthesis of raw material medicines and the raw material medicines contained in the preparation after the raw material medicines. The invention researches a detection method capable of comprehensively detecting related substances of dabigatran etexilate mesylate and a preparation thereof.
The invention mainly solves the technical problem that the existing detection method for dabigatran etexilate mesylate or related substances of a preparation thereof can only detect degradation impurities of capsules, and a plurality of related substance impurities can not be detected. In order to solve the technical problem, the technical scheme is as follows: the detection method for the related substances of the dabigatran etexilate mesylate or the preparation thereof is characterized by adopting high performance liquid chromatography for detection, and performing qualitative or quantitative detection on the related substances, wherein the detection conditions comprise:
a chromatographic column: octadecylsilane chemically bonded silica gel column, detection wavelength: 210-400 nm, mobile phase: a mobile phase A: a water phase containing a buffer solution, wherein the pH is 4.25-4.40, and further 4.3; the mobile phase B mainly comprises methanol or acetonitrile; the mobile phase is eluted by a gradient elution method.
Further, the related substances at least comprise: one or more of the impurities 8, 4 and 1, and further, the related substances at least comprise one or more of the impurities 02, 5, 7, 9, 2, 10, 11 and 12.
Further, the mobile phase elution gradient is as follows:
in one embodiment of the invention, the mobile phase elution gradient is as follows:
on the basis of determining the chromatographic column packing, the size of the chromatographic column can be conventional, namely the length of the chromatographic column is 50-250 mm, the inner diameter of the chromatographic column is 2.1-4.6 mm, and the particle size of the packing is 3-5 mu m. In one embodiment of the invention, the length is 250mm, the inner diameter is 4.6mm, and the particle size is 5 μm.
The wavelengths to be detected in the present invention can be adjusted and selected by conventional means within the range disclosed above. When the optimal detection wavelength is searched, the method can be carried out by using a full-wave-band scanning method and the like which are matched with an ultraviolet spectrophotometry method and HPLC, and then the appropriate detection wavelength is found by adopting a conventional technology by matching with the detection effect of an HPLC detector (such as avoiding solvent interference). In one embodiment of the present invention, the detection wavelength is selected from 210 to 400nm, for example at 242nm, 310nm or/and 340 nm.
Further, the pH of the aqueous phase was 4.3.
Wherein the buffer is an acetate-acetic acid buffer. A phosphoric acid buffer system is tried in the early stage, the separation effect is not ideal, and only acetate is good in separation effect.
The acetate in the acetate-acetic acid buffer solution of the present invention includes, but is not limited to, sodium acetate, potassium acetate, or ammonium acetate. Further, the acetate is selected from ammonium acetate; furthermore, the concentration of ammonium acetate in the buffer solution is 0.2 wt% to 0.5 wt%, preferably 0.2 wt%. The buffer solution is prepared by taking an acetate solution with proper concentration and adding acetic acid to adjust the pH value.
Further, the mobile phase B mainly comprises acetonitrile.
In the invention, the parameters such as column temperature, flow rate, sample injection amount and the like can be selected in a common range.
Further, the flow rate of the mobile phase is 0.8ml/min to 1.2ml/min, for example, 1.0 ml/min.
Further, the column temperature is selected from 20-40 ℃, and is further selected from 25-35 ℃, such as 35 ℃.
Further, the detection method comprises the following steps:
(1) preparing a test solution and a reference solution;
(2) respectively injecting sample solution for test and reference solution for detection, and shaping or quantifying related substances.
The preparation of the test solution and the reference solution is not limited in sequence.
The invention also provides a method for detecting the content of the dabigatran etexilate mesylate or the preparation thereof, the detection method adopts high performance liquid chromatography for detection, and carries out qualitative or quantitative detection on the dabigatran etexilate mesylate, and the detection conditions comprise: a chromatographic column: octadecylsilane chemically bonded silica gel column, detection wavelength: 210-400 nm, mobile phase: mobile phase A: a water phase containing a buffer solution, the pH of which is 4.25 to 4.40, further 4.3; the mobile phase B mainly comprises methanol or acetonitrile; the mobile phase is eluted by a gradient elution method, wherein the elution gradient of the gradient elution method is as follows:
the other conditions are the same as the impurity detection method.
The qualitative detection in the present invention can be performed by using conventional methods, such as corresponding analysis by external standard method with reference substance, or qualitative analysis by conventional identification means, such as mass spectrum, thin layer, ultraviolet, etc. after separating each component by HPLC.
In the invention, the content can be calculated by using the conventional methods such as an external standard method, an area normalization method and the like.
During quantitative analysis, if an external standard method is used, a standard curve is manufactured by a conventional method for calculation; however, in the qualitative analysis, a standard curve is not required to be prepared, and the determination can be made by the retention time.
The specific names and structures of the impurities 02, 5, 7, 9, 1, 2, 4, 8, 10, 11 and 12 are as follows:
the invention has the beneficial effects that: by adopting the detection method for the dabigatran etexilate mesylate and the related substances of the preparation thereof, the degradation impurities of the dabigatran etexilate mesylate and the preparation thereof can be detected, and the process impurities brought in the synthesis process of the dabigatran etexilate mesylate can also be detected; the detection method can separate chromatographic peaks of related substances of the dabigatran etexilate mesylate and the preparation thereof, and has good chromatographic peak separation degree.
Drawings
FIG. 1 shows a systematic adaptive chromatogram of the detection method of related substances of dabigatran etexilate mesylate of the invention.
FIG. 2 is a systematic adaptive chromatogram of an import dabigatran etexilate mesylate registration standard detection method.
FIG. 3 chromatogram of example 1 of detection method of related substances of dabigatran etexilate mesylate.
FIG. 4 chromatogram of example 2 of detection method of dabigatran etexilate mesylate related substances
FIG. 5 chromatogram of embodiment 2 of the method for detecting the content of dabigatran etexilate mesylate.
In the graphs of FIGS. 1 and 2, DBC-Z8 is impurity 8, DBC-Z4 is impurity 4, and DBC-Z1 is impurity 1.
Detailed Description
Example 1
Chromatographic conditions and system applicability test a chromatographic column (Phenomenex Gemini C18, 4.6X 250mm, 5 μm is recommended) using octadecylsilane chemically bonded silica as a filler, 0.2% ammonium acetate solution (pH adjusted to 4.3 with glacial acetic acid) as a mobile phase A, acetonitrile as a mobile phase B, and gradient elution was performed according to the following table; the column temperature is 35 ℃, the flow rate is 1.0ml/min, and the detection wavelengths are 242nm, 310nm and 340 nm.
Taking 6 reference substances as impurities, accurately weighing, dissolving with diluent 1[ acetonitrile-ethanol-water (12:3:10) ] and diluting with diluent 2[ mobile phase A-mobile phase B (85:15) ] to obtain solution containing 0.3mg per 1ml as reference substance solution (1); precisely weighing reference substances of impurity 02, impurity 5, impurity 7, impurity 9, impurity 1, impurity 2, impurity 4, impurity 8, impurity 10, impurity 11 and impurity 12, dissolving with the above diluent 1, and diluting with diluent 2 to obtain solution containing about 90 μ g of each impurity per 1ml as reference solution (2). Taking 30mg of the product, accurately weighing, placing in a 100ml volumetric flask, dissolving with the above diluent 1, adding 1ml of each of the reference substance solutions (1) and (2), diluting to scale with the above diluent 2, and shaking to obtain system applicability solution. Precisely 50. mu.L of the solution was injected into a liquid chromatograph, and a chromatogram (shown in FIG. 1, DBC-Z8, DBC-Z4, and DBC-Z1, i.e., impurity 8, impurity 4, and impurity 1) was recorded.
The determination method comprises dissolving dabigatran etexilate mesylate capsule with diluent 1[ acetonitrile-ethanol-water (12:3:10) ] and diluting with diluent 2[ mobile phase A-mobile phase B (85:15) ] to obtain solution containing 0.3mg per 1ml as sample solution; precisely measuring 1.0ml of the test solution, placing the test solution into a 100ml measuring flask, diluting the test solution to a scale with a diluent 2, and shaking up to obtain a reference solution. The sample solution and the control solution were precisely measured at 50. mu.L each and injected into a liquid chromatograph, and the chromatogram was recorded, as shown in FIG. 3.
Comparative example
Chromatographic conditions and system applicability test a chromatographic column using octadecylsilane chemically bonded silica as a filler, taking 0.2% ammonium acetate solution (pH value is adjusted to 4.4 by glacial acetic acid) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table; the column temperature was 40 ℃ and the flow rate was 2.0ml/min, using a DAD detector, the detection wavelength was 340 nm.
The results of the detection of the system-compatible solution of example 1 using the chromatographic conditions are shown in FIG. 2, in which DBC-Z8, DBC-Z4 and DBC-Z1 are impurity 8, impurity 4 and impurity 1.
Example 2
Chromatographic conditions and system applicability test a chromatographic column (Phenomenex Gemini C18, 4.6X 250mm, 5 μm is recommended) using octadecylsilane chemically bonded silica as a filler, 0.3% ammonium acetate solution (pH adjusted to 4.3 with glacial acetic acid) as a mobile phase A, acetonitrile as a mobile phase B, and gradient elution was performed according to the following table; the column temperature is 35 ℃, the flow rate is 1.0ml/min, and the detection wavelengths are 242nm, 310nm and 340 nm.
Taking 6 reference substances as impurities, accurately weighing, dissolving with 1[ acetonitrile-ethanol-water (12:3:10) ] diluent, and diluting with 2[ mobile phase A-mobile phase B (85:15) ] diluent to obtain solution containing 0.3mg per 1ml as reference substance solution (1); precisely weighing reference substances of impurity 02, impurity 5, impurity 7, impurity 9, impurity 1, impurity 2, impurity 4, impurity 8, impurity 10, impurity 11 and impurity 12, dissolving with the above diluent 1, and diluting with diluent 2 to obtain solution containing about 90 μ g of each impurity per 1ml as reference solution (2). Taking 30mg of the product, accurately weighing, placing in a 100ml volumetric flask, dissolving with the above diluent 1, adding 1ml of each of the reference substance solutions (1) and (2), diluting to scale with the above diluent 2, and shaking to obtain system applicability solution. Precisely measuring 50 μ L, injecting into a liquid chromatograph, recording chromatogram, and detecting results as shown in FIG. 4 as follows:
when the content of dabigatran etexilate mesylate is measured by the method, a map is shown in FIG. 5.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes, which are made by the present specification, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (14)
1. A detection method of dabigatran etexilate mesylate or related substances of a preparation thereof is characterized in that the detection method adopts high performance liquid chromatography for detection, and qualitative or quantitative detection is carried out on related substances;
the related substances also at least comprise one or more of impurities 4, 10 and 11;
impurity 4:
10 parts of impurities:
impurity 11:
the detection conditions include:
a chromatographic column: octadecylsilane chemically bonded silica gel column, detection wavelength: 210-400 nm, mobile phase: mobile phase A: a water phase containing a buffer solution, wherein the buffer solution is an acetate-acetic acid buffer solution, and the pH value is 4.25-4.40; the mobile phase B mainly comprises methanol or acetonitrile; the mobile phase is eluted by a gradient elution method, and the elution procedure is as follows:
2. the method for detecting dabigatran etexilate mesylate or a substance related to a formulation thereof according to claim 1, wherein the pH is 4.3.
3. The method for detecting the dabigatran etexilate mesylate or the preparation related substances thereof according to claim 1, wherein the related substances at least comprise: one or more of impurity 8 and impurity 1;
impurity 8:
impurity 1:
。
4. the method for detecting dabigatran etexilate mesylate or a preparation related substance thereof according to claim 1 or 3, wherein the related substance further comprises at least one or more of impurity 02, impurity 2, impurity 5, impurity 6, impurity 7, impurity 9 and impurity 12;
impurity 02:
impurity 2:
impurity 5:
impurity 6:
impurity 7:
impurity 9:
impurity 12:
。
5. the method for detecting dabigatran etexilate mesylate or a related substance of a preparation thereof according to claim 1, wherein an elution gradient of the gradient elution method is as follows:
6. the method for detecting dabigatran etexilate mesylate or a preparation related substance thereof according to claim 1, wherein the size of the chromatographic column is 4.6 x 250mm, 5 μm.
7. The method for detecting dabigatran etexilate mesylate or a preparation-related substance thereof according to claim 1, wherein the detection wavelength is 242nm, 310nm or/and 340 nm.
8. The method for detecting dabigatran etexilate mesylate or a preparation-related substance thereof according to claim 1, wherein the acetate salt is selected from sodium acetate and ammonium acetate.
9. The method for detecting dabigatran etexilate mesylate or a preparation related substance thereof according to claim 8, wherein the concentration of ammonium acetate in the buffer solution is 0.2 wt% to 0.5 wt%.
10. The method for detecting dabigatran etexilate mesylate or a substance related to a formulation thereof according to claim 9, wherein the ammonium acetate concentration in the buffer solution is 0.2 wt%.
11. The method for detecting dabigatran etexilate mesylate or a preparation related substance thereof according to claim 1 or 5, wherein the mobile phase B mainly comprises acetonitrile.
12. The method for detecting dabigatran etexilate mesylate or a related substance of a preparation thereof according to claim 1, wherein the detection conditions further comprise a flow rate, wherein the flow rate is 0.8ml/min to 1.2 ml/min; the detection condition further comprises a column temperature, and the column temperature is 28-40 ℃.
13. The method for detecting dabigatran etexilate mesylate or a substance related to the preparation thereof according to claim 12, wherein the flow rate is 1.0 ml/min; the column temperature was 35 ℃.
14. The method for detecting dabigatran etexilate mesylate or a preparation related substance thereof according to claim 1, wherein the method comprises the following steps:
(1) preparing a test solution and a reference solution;
(2) respectively injecting sample solution and reference solution for detection, and performing qualitative or quantitative determination on related substances.
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| CN113933400B (en) * | 2020-06-29 | 2024-01-12 | 石药集团恩必普药业有限公司 | Detection method of genotoxic impurities in dabigatran etexilate bulk drug or preparation |
| CN114264749A (en) * | 2021-12-27 | 2022-04-01 | 卓和药业集团股份有限公司 | Analysis and detection method of dabigatran etexilate |
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