CN110187036B - Bivalirudin raw material and quality control method of preparation thereof - Google Patents
Bivalirudin raw material and quality control method of preparation thereof Download PDFInfo
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Abstract
The invention provides a bivalirudin raw material and a quality control method of a bivalirudin preparation, which are characterized in that a test solution containing the bivalirudin raw material or a test solution containing the bivalirudin preparation is detected by high performance liquid chromatography to obtain the content of each bivalirudin and impurities in a substance to be detected; the detection method has the advantages that the mobile phase detected by the high performance liquid chromatography is selected to be the mixed liquid of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile, so that the detection method can effectively realize good separation of bivalirudin and impurities, the detection method is stable, the result is accurate, the loss of a chromatographic column is small, and the service life of the chromatographic column can be prolonged.
Description
Technical Field
The invention relates to the field of pharmaceutical analysis, in particular to a bivalirudin raw material and a quality control method of a bivalirudin preparation.
Background
Bivalirudin (CAS No.: 128270-60-0, molecular formula: C)98H138N24O33Molecular weight: 2180.29) is a synthetic hirudin analogue consisting of 20 amino acid residues which directly inhibits thrombin activity, recognizes the binding site of thrombin and fibrinogen and thereby inhibits thrombin activity. At present, no quality control method for bivalirudin raw materials and preparations thereof is reported, and the establishment of a stable and reliable quality control method for the raw materials and the preparations thereof has great significance.
The difference of polypeptide chain constitution directly influences the establishment of the detection method, and at present, the polypeptide detection method comprises High Performance Liquid Chromatography (HPLC), Mass Spectrometry (MS), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis-mass spectrometry (CE-MS), spectroscopic analysis and the like. When a polypeptide is detected by High Performance Liquid Chromatography (HPLC), the following problems exist: (1) the detection of the polypeptide has higher requirements on the composition and the pH value of a mobile phase; (2) the separation degree can not meet the requirement; (3) the polypeptide is readily adsorbed to the filler.
For example, in the currently disclosed method for measuring related substances and contents in the bivalirudin quality standard for injection with the drug standard number YBH01662016, 0.1mol/L sodium acetate buffer (8.2 g of anhydrous sodium acetate is taken and about 900ml of water is added for dissolution, the pH value is adjusted to 6.5 by acetic acid, the solution is diluted to 1000ml) by adding water to form a mobile phase A by using water (50: 50), and 0.1mol/L sodium acetate buffer-acetonitrile (50: 50) to form a mobile phase B by using the following table for gradient elution, wherein the flow rate is 1.2ml/min, the column temperature is 40 ℃, and the detection wavelength is 215 nm. Tests prove that the mobile phase of the enterprise has the following defects: (1) after the mobile phase is used for multiple times, the chromatographic column is damaged, the column efficiency is low, the service life of the chromatographic column is shortened, the scientific research cost is increased, and (2) the content determination is inconsistent with the liquid phase determination method of related substances, and different mobile phases are used for detecting related substance impurities I, II and III, the operation is complicated, the calculation is complex, and (3) only three impurities are detected in the standard, but the determination method of other two impurities is not seen, namely the related substance detection is incomplete.
Through literature search, there is also a report on the determination of 6 related substances in bivalirudin for injection by gradient elution using high performance liquid chromatography, a column YMC-Pack ODS-AM (250 mm. times.4.6 mm, 5 μm) using octadecylsilane chemically bonded silica as a packing material, a column temperature of 30 ℃, a wavelength of 210nm, a sample size of 20 μ L, a phosphate solution of 5mmol/L (pH adjusted to 3.5 with phosphoric acid) as a mobile phase A, and acetonitrile as a mobile phase B, as seen from the chromatogram. It has also been reported that the content of veratridine and related substances was measured using Diamonsil C18 column (250 mm. times.4.6 mm, 5 μm), 5mmol/L potassium dihydrogen phosphate (pH adjusted to 2.5 with phosphoric acid solution) and acetonitrile (80: 20) as mobile phase at a flow rate of 1mL/min and a detection wavelength of 210 nm. After rechecking, the method still has the problem that the chromatographic column is damaged after the mobile phase is used for many times, so that the column efficiency is low, the service life of the chromatographic column is shortened, and the scientific research cost is increased.
Therefore, it is of great significance to provide a method which can accurately evaluate the quality of a raw material of vardendine and a preparation thereof and can prolong the service life of a chromatographic column.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a quality control method for bivalirudin raw material and its preparation, which can effectively separate each impurity from the main peak of the raw material, and has a long service life of the chromatographic column.
Compared with the prior art, the invention provides a bivalirudin raw material and a quality control method of a bivalirudin preparation, and the content of each raw material and impurities in a substance to be detected is obtained by detecting a test solution containing the bivalirudin raw material or a test solution containing the bivalirudin preparation through high performance liquid chromatography; the detection method has the advantages that the mobile phase detected by the high performance liquid chromatography is selected to be the mixed liquid of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile, experiments show that the detection method can effectively realize good separation of bivalirudin and impurities, the detection method is stable, the result is accurate, the loss of a chromatographic column is small, and the service life of the chromatographic column can be prolonged.
Drawings
FIG. 1 is an HPLC chart of a test solution for measuring bivalirudin content for injection;
FIG. 2 is an HPLC chart of a bivalirudin control solution;
FIG. 3 is an HPLC chart of a mixed control solution;
FIG. 4 shows the HPLC results of the control solution for checking bivalirudin related substance for injection;
FIG. 5 shows HPLC results of a test solution for detecting bivalirudin related substances for injection.
Detailed Description
The invention provides a bivalirudin raw material and a quality control method of a bivalirudin preparation, which are characterized in that a test solution containing the bivalirudin raw material or a test solution containing the bivalirudin preparation is detected by high performance liquid chromatography to obtain the content of the bivalirudin and impurities in a substance to be detected;
wherein, the mobile phase detected by the high performance liquid chromatography is the mixed liquid of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile.
In the invention, the solvent in the test solution containing bivalirudin raw materials or the test solution containing bivalirudin preparations is water, wherein in the bivalirudin content determination method, the concentration of the bivalirudin raw materials or the preparations containing bivalirudin in the test solution is preferably 0.05mg/ml-0.2mg/ml, and more preferably 0.1 mg/ml; in the method for determining bivalirudin related substances, the concentration of the bivalirudin raw material or the bivalirudin preparation in the test solution is preferably 1.5mg/ml-2.5mg/ml, more preferably 2mg/ml, and the control solution is prepared by diluting the test solution by 500 times.
In the invention, the volume ratio of the trifluoroacetic acid, the water, the tetrahydrofuran and the acetonitrile in the mobile phase detected by the high performance liquid chromatography provided by the invention is preferably (1-2): (700-900): (80-200), more preferably (1-2): (800-850): (100-150): 100-150), and most preferably 2: 800: 100.
In the invention, the filler of the chromatographic column for high performance liquid chromatography detection is octadecylsilane bonded silica gel, and the chromatographic column with the filler of the octadecylsilane bonded silica gel is preferably a Kinetex XB-C18 chromatographic column, a Welch Ultimate XB-C18 chromatographic column, a Waters Symmetry C18 chromatographic column, an Agilent Zorbax XB-C18 chromatographic column, a Phenomenex Luna C18 chromatographic column or an Altima C18 chromatographic column.
In the invention, the wavelength of the high performance liquid chromatography detection is preferably 203-215 nm, and more preferably 210 nm; the detector of the high performance liquid chromatography is preferably an ultraviolet detector; the bivalirudin content determination method is characterized in that the number of theoretical plates detected by the high performance liquid chromatography is not less than 5000 according to the bivalirudin peak calculation.
In the present invention, the flow rate of the mobile phase detected by the high performance liquid chromatography is preferably 0.4 to 1.0ml/min, and more preferably 0.6 to 0.8 ml/min.
In the invention, the column temperature detected by the high performance liquid chromatography is preferably 25-70 ℃, more preferably 40-60 ℃, and most preferably 50 ℃.
In the invention, the external standard method for the content determination method in the high performance liquid chromatography detection specifically comprises the following steps:
and (2) analyzing a mixed reference substance solution (hereinafter referred to as a mixed reference substance solution) of bivalirudin and known impurities, a reference substance solution (hereinafter referred to as a reference substance solution) of bivalirudin and a test solution of a bivalirudin raw material or a test solution (hereinafter collectively referred to as a test solution) containing a bivalirudin preparation by using a high performance liquid chromatograph, and calculating the content of the bivalirudin by using a peak area according to an external standard method.
The method for measuring the related substances comprises the following steps:
and (3) analyzing a mixed reference substance solution of bivalirudin and known impurities, a test solution of a bivalirudin raw material or a test solution containing a bivalirudin preparation and a reference solution by using a high performance liquid chromatograph, calculating the known impurities in a chromatogram of the test solution by using a peak area according to an external standard method, and calculating the unknown impurities by using a main component self-reference method to obtain the content of related substances. Wherein, in the step of detecting the content of related substances, the concentration of the bivalirudin in the mixed reference substance solution is preferably 0.05mg/ml to 3mg/ml, more preferably 1.0mg/ml to 3.0mg/ml, and more preferably 2.0 mg/ml. The concentration of each known impurity in the mixed control solution is preferably 1 to 10. mu.g/ml, more preferably 2 to 15. mu.g/ml, and still more preferably 10. mu.g/ml. The concentration of the control solution is preferably 0.1. mu.g/ml to 6. mu.g/ml, more preferably 2. mu.g/ml to 6. mu.g/ml, and still more preferably 4. mu.g/ml.
In the step of detecting the content of the bivalirudin raw material and related substances of the preparation thereof, the time of analyzing the mixed reference solution, the reference solution and the test solution in the liquid chromatogram is more than 2 times of the retention time of the bivalirudin main component peak. The other conditions of the liquid chromatograph are the same as those of the liquid chromatograph in the content measurement of the raw material and the preparation of the test bivalirudin.
The invention provides a bivalirudin raw material and a quality control method of a bivalirudin preparation, which are characterized in that a test solution containing the bivalirudin raw material or a test solution containing the bivalirudin preparation is detected by a high performance liquid chromatography to obtain the content of each raw material and impurities in a substance to be detected; the detection method has the advantages that the mobile phase detected by the high performance liquid chromatography is selected to be the mixed liquid of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile, and the result shows that the detection method not only can effectively realize good separation of bivalirudin and impurities, but also is stable, accurate in result, low in loss to a chromatographic column and capable of prolonging the service life of the chromatographic column.
The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The instrument used was: an Agilent1260 high performance liquid chromatograph comprises a G1311C quaternary gradient pump, a vacuum degasser, a G1329B autosampler, a G1314F ultraviolet detector and a G1316A column incubator, wherein a chromatographic column is Kinetex XB-C18 and is 4.6mm multiplied by 150 mm.
Octadecylsilane chemically bonded silica is used as a filling agent, and a trifluoroacetic acid-water-tetrahydrofuran-acetonitrile mixed solution is used as a mobile phase, wherein in the mixed solution, the trifluoroacetic acid-water-tetrahydrofuran-acetonitrile is 2: 800: 100 according to the volume ratio, the detection wavelength is 210nm, the column temperature is 50 ℃, the flow rate is 0.6ml/min, and the number of theoretical plates is not less than 5000 according to the ratio of vardine peak.
Taking a test sample, adding water to dissolve and dilute the test sample to obtain a solution with the concentration of 0.1mg/ml as a test sample solution, measuring 10 mu l of the test sample solution, injecting the solution into a liquid chromatograph, and recording a chromatogram, wherein the result is shown in figure 1, and figure 1 is an HPLC (high performance liquid chromatography) diagram of the test sample solution for measuring the content of bivalirudin for injection;
taking bivalirudin reference substance (content 88.0%) purchased from Douchnero Biotechnology Co., Ltd, adding water to dissolve and dilute to obtain solution with concentration of 0.1mg/ml, using as reference substance solution, measuring 10 μ l of the reference substance solution, injecting into a liquid chromatograph, recording chromatogram, and obtaining the result shown in figure 2, and figure 2 is HPLC chart of the bivalirudin reference substance solution.
The content was calculated using the external standard method: the content of the test sample is obtained by calculating the ratio of the peak areas of the test sample solution and the reference solution, and the content determination result is shown in the following table.
Table 1 chromatographic analysis results of test solutions of bivalirudin raw material and formulation thereof in example 1
| Name (R) | Retention time (min) | Peak area | Content% |
| Bivalirudin raw material | 34.619 | 1687.87634 | 109.15 |
| Bivalirudin for injection | 36.874 | 1743.23965 | 99.07 |
Example 2
The chromatograph, the filler and the mobile phase used were the same as in example 1.
Taking appropriate amount of BIVA (12-20) -BIVA, Plus-Gly-BIVA, Des-Gly-BIVA, Beta-Asp9-BIVA, Alpha-Asp9-BIVA impurity reference substances and bivalirudin, dissolving with water and diluting to prepare a mixed reference substance solution containing 10 mu g/ml of each impurity and 2mg/ml of bivalirudin; dissolving bivalirudin raw material and preparation samples thereof with water to prepare a test solution of 2.0 mg/ml; a portion of the test solution was diluted with water to make a 4.0. mu.g/ml control solution.
Injecting 10 mu l of each of the mixed reference solution, the reference solution and the test solution into a liquid chromatograph for detection, recording a chromatogram until the retention time of a main component peak is more than 2 times, wherein the detection results are shown in figures 3-5, the figure 3 is an HPLC (high performance liquid chromatography) diagram of the mixed reference solution, the figure 4 is an HPLC result of the reference solution for detecting the bivalirudin related substances for injection, and the figure 5 is an HPLC result of the test solution for detecting the bivalirudin related substances for injection; the specific data results are shown in tables 2-4 below.
Table 2 peak signal of solution for system applicability in example 2
| Composition (I) | Retention time (min) | Peak area | Degree of separation |
| BIVA(12-20)-BIVA | 20.378 | 199.18544 | - |
| Plus-Gly-BIVA | 34.445 | 190.66193 | 19.22 |
| Bivalirudin | 35.356 | 31394 | 0.54 |
| Des-Gly-BIVA | 40.284 | 123.66733 | 2.51 |
| Beta-Asp9-BIVA | 41.609 | 129.90733 | 0.95 |
| Alpha-Asp9-BIVA | 46.397 | 134.09659 | 3.77 |
TABLE 3 examination results of bivalirudin for injection in example 2
TABLE 4 test solutions for examination of bivalirudin related substances for injection
Calculating to obtain bivalin serving as an impurity in bivalirudin raw materials(12-20)The BIVA content is less than 0.2%, no other impurities are detected; BIVA as impurity in bivalirudin for injection (batch: 20190226)(12-20)The BIVA content is less than 0.2%, and the content of other single impurities is less than 0.2%.
From the results, the detection method provided by the invention can well separate each impurity in the bivalirudin raw material. And the analysis of the use record shows that the chromatographic column can still be normally used for more than 3 months by using the detection method provided by the invention. The detection scheme mentioned in the background art has the advantages that the service life of the chromatographic column is not more than 1 month under the condition of the same daily use frequency of the application.
Example 3
The instrument used was: the Agilent1200 high performance liquid chromatograph comprises a G1322A quaternary gradient pump, a G1311A vacuum degasser, a G1329A autosampler, a G1316A ultraviolet detector, a G1314B column incubator, and a chromatographic column of Agilent ZorbaxXB-C18.
Octadecylsilane chemically bonded silica is used as a filling agent, a trifluoroacetic acid-water-tetrahydrofuran-acetonitrile mixed solution is used as a mobile phase, in the mixed solution, the trifluoroacetic acid-water-tetrahydrofuran-acetonitrile is 1.5: 700: 150 according to the volume ratio, the detection wavelength is 208nm, the column temperature is 30 ℃, the flow rate is 0.8ml/min, and the number of theoretical plates is not less than 5000 according to the ratio of vardine peak.
Taking a test sample, adding water to dissolve and dilute the test sample to obtain a solution with the concentration of 0.1mg/ml as a test sample solution, measuring 10 mu l of the test sample solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
Collecting bivalirudin reference substance (content 88.0%) purchased from Chengdu Shengnuo Biotechnology Ltd, adding water
Dissolving and diluting to obtain a solution with the concentration of 0.1mg/ml, taking the solution as a reference solution, measuring 10 mu l of the reference solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
The content was calculated using the external standard method: the content of the test sample is obtained by calculating the ratio of the peak areas of the test sample solution and the reference solution, and the content determination result is shown in the following table.
Table 4 chromatographic analysis results of bivalirudin test sample solution for injection in example 3
| Name (R) | Retention time (min) | Peak area | Content% |
| Bivalirudin for injection | 30.547 | 1784.98735 | 104.50 |
Example 4
The instrument used was: an Agilent1100 high performance liquid chromatograph comprises a G1379A quaternary gradient pump, a G1311A vacuum degasser, a G1313A autosampler, a G1316A ultraviolet detector, a G1315B column incubator, and a chromatographic column of PhenomenexLuna C18.
Octadecylsilane chemically bonded silica is used as a filling agent, a trifluoroacetic acid-water-tetrahydrofuran-acetonitrile mixed solution is used as a mobile phase, in the mixed solution, the trifluoroacetic acid-water-tetrahydrofuran-acetonitrile is 1: 750: 125 according to the volume ratio, the detection wavelength is 213nm, the column temperature is 40 ℃, the flow rate is 1.0ml/min, and the number of theoretical plates is not less than 5000 according to the ratio of vardine peak.
Taking a test sample, adding water to dissolve and dilute the test sample to obtain a solution with the concentration of 0.1mg/ml as a test sample solution, measuring 10 mu l of the test sample solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
Taking a bivalirudin reference substance (with the content of 88.0%) purchased from Douchnero Biotechnology Co., Ltd, adding water to dissolve and dilute the reference substance to obtain a solution with the concentration of 0.1mg/m1, taking the solution as a reference substance solution, measuring 10 mu 1 of the reference substance solution, injecting the solution into a liquid chromatograph, and recording a chromatogram.
The content was calculated using the external standard method: the content of the test sample is obtained by calculating the ratio of the peak areas of the test sample solution and the reference solution, and the content result is shown in the following table.
TABLE 5 chromatographic analysis results of bivalirudin test solution for injection in example 4
| Name (R) | Retention time (min) | Peak area | Content% |
| Bivalirudin for injection | 23.879 | 1809.12748 | 103.98 |
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (5)
1. A quality control method for bivalirudin raw material and its preparation comprises detecting test solution containing bivalirudin raw material or test solution containing bivalirudin preparation by high performance liquid chromatography to obtain the content of bivalirudin and impurities in the substance to be detected;
wherein, the mobile phase detected by the high performance liquid chromatography is the mixed solution of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile;
the volume ratio of trifluoroacetic acid, water, tetrahydrofuran and acetonitrile in the mobile phase is 1-2: 800-850: 100-150: 100-150;
the wavelength of the high performance liquid chromatography detection is 203-215 nm;
the flow rate of the mobile phase detected by the high performance liquid chromatography is 0.4-1.0 ml/min;
the filler of the chromatographic column for high performance liquid chromatography detection is octadecylsilane chemically bonded silica;
the impurities comprise BIVA(12-20)-BIVA、Plus-Gly-BIVA、Des-Gly-BIVA、Beta-Asp9BIVA and Alpha-Asp9-BIVA。
2. The quality control method according to claim 1, wherein the column chromatography of which the filler is octadecylsilane bonded silica gel is a Kinetex XB-C18 column chromatography, a Welch Ultimate XB-C18 column chromatography, a Waters Symmetry C18 column chromatography, an Agilent Zorbax XB-C18 column chromatography, a Phenomenex Luna C18 column chromatography, or an altima C18 column chromatography.
3. The quality control method according to claim 1, wherein the number of theoretical plates for content measurement by HPLC is not less than 5000 in terms of bivalirudin peak.
4. The quality control method according to claim 1, wherein the column temperature detected by high performance liquid chromatography is 25-70 ℃.
5. The quality control method according to claim 1, wherein the determination method of bivalirudin content in the high performance liquid chromatography detection specifically comprises the following steps:
analyzing a mixed reference substance solution of bivalirudin and known impurities, a reference substance solution of bivalirudin and a test solution of a bivalirudin raw material or a test solution containing a bivalirudin preparation by a high performance liquid chromatograph, and calculating peak area according to an external standard method to obtain the content of the bivalirudin;
the method for measuring the content of the related substances in the high performance liquid chromatography detection specifically comprises the following steps:
and (3) analyzing a mixed reference substance solution of bivalirudin and known impurities, a test solution of a bivalirudin raw material or a test solution containing a bivalirudin preparation and a reference solution by using a high performance liquid chromatograph, calculating the known impurities in a chromatogram of the test solution by using a peak area according to an external standard method, and calculating the unknown impurities by using a main component self-reference method to obtain the content of related substances.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260323A (en) * | 2011-05-30 | 2011-11-30 | 杭州诺泰制药技术有限公司 | Method for preparing bivalirudin by combining solid phase with liquid phase and detection method |
| CN105223296B (en) * | 2015-10-16 | 2017-12-05 | 江苏开元药业有限公司 | The purification process of a kind of polypeptide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260323A (en) * | 2011-05-30 | 2011-11-30 | 杭州诺泰制药技术有限公司 | Method for preparing bivalirudin by combining solid phase with liquid phase and detection method |
| CN105223296B (en) * | 2015-10-16 | 2017-12-05 | 江苏开元药业有限公司 | The purification process of a kind of polypeptide |
Non-Patent Citations (4)
| Title |
|---|
| Liquid chromatography-high resolution mass spectrometry for peptide drug quality control;Zeng K 等;《The AAPS journal》;20150226;第17卷(第3期);第643-651页 * |
| 反相HPLC法测定注射用比伐卢定中6种有关物质;王长平 等;《沈阳药科大学学报》;20180531;第35卷(第5期);第367-373页 * |
| 反相高效液相色谱法测定注射用比伐卢定中的[Asp~9]-比伐卢定;张勇纯 等;《临床医药文献电子杂志》;20180930;第5卷(第75期);第8-11页 * |
| 比伐卢定氨基酸组成比测定方法的改进;陈华;《中国生化药物杂志》;20101031;第31卷(第5期);第338-340页 * |
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