CN115248260A - HPLC analysis detection method for related substances in cisatracurium besilate bulk drug - Google Patents

HPLC analysis detection method for related substances in cisatracurium besilate bulk drug Download PDF

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CN115248260A
CN115248260A CN202110463028.9A CN202110463028A CN115248260A CN 115248260 A CN115248260 A CN 115248260A CN 202110463028 A CN202110463028 A CN 202110463028A CN 115248260 A CN115248260 A CN 115248260A
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bsa
mobile phase
related substances
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cisatracurium besilate
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张健
涂波
王洪芳
朱志雄
马仕珉
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SUZHOU LANXITE BIOTECHNOLOGY CO Ltd
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    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/86—Signal analysis
    • G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
    • G01N30/8679—Target compound analysis, i.e. whereby a limited number of peaks is analysed
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities

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Abstract

The invention belongs to the technical field of analytical chemistry, and particularly discloses a method for detecting related substances in cisatracurium besilate bulk drugs, and more particularly discloses a method for specially analyzing and detecting BSA2, BSA-B, BSA-C, BSA-D, BSA-E, BSA-F, BSA-G, BSA-H, BSA-U, BSA-L, BSA-J, BSA-M, BSA-I and BSA-K or medicines containing 14 substances in the cisatracurium besilate bulk drugs. The method optimizes the conditions of the composition of the buffer salt, the selection of the pH regulator, the pH value of the solution, the gradient elution procedure and the like, finally establishes a proper analysis method, can achieve baseline separation between the main component and each related substance and between the related substances, and has strong specificity, good reproducibility and high accuracy.

Description

HPLC analysis detection method for related substances in cisatracurium besilate bulk drug
Technical Field
The invention belongs to the technical field of analytical chemistry, and particularly relates to a method for determining related substances in cisatracurium besilate bulk drugs by using HPLC (high performance liquid chromatography), and more particularly discloses a method for specially analyzing and detecting BSA2, BSA-B, BSA-C, BSA-D, BSA-E, BSA-F, BSA-G, BSA-H, BSA-U, BSA-L, BSA-J, BSA-M, BSA-I and BSA-K or medicines containing 14 substances in the cisatracurium besilate bulk drugs.
Background
The related substances are one of the key items in the medicine quality research, and are closely related to the stability of the process, the quality, the safety and the curative effect of the medicine. The existence of related substances may reduce the curative effect of the medicine and even cause toxic and side effects, so that a proper detection and analysis method must be established to truly reflect the related substances in the medicine and ensure the quality of the medicine.
Cisatracurium besilate is a neuromuscular blocking agent that binds to cholinergic receptors on the motor endplates to antagonize the action of acetylcholine, thereby producing a competitive neuromuscular transmission blocking effect. The product can be used for operation and other operations and intensive care therapy. Can be used as adjuvant medicine for general anesthesia or has tranquilizing effect in Intensive Care Unit (ICU), and can relax smooth muscle to facilitate tracheal intubation and mechanical ventilation.
14 related substances, namely BSA2, BSA-B, BSA-C, BSA-D, BSA-E, BSA-F, BSA-G, BSA-H, BSA-U, BSA-L, BSA-J, BSA-M, BSA-I and BSA-K can be generated in the production process of the cisatracurium besilate bulk drug. The content of the 14 related substances directly influences the quality of the cisatracurium besilate or metabolites thereof, and is easy to cause adverse reaction of human bodies and generate irritation of medicines. The Chinese pharmacopoeia and the United states pharmacopoeia both have HPLC detection methods for collecting cis atracurium besilate related substances, but the Chinese pharmacopoeia only controls 2 impurities, BSA-U in the United states pharmacopoeia completely coincides with a key intermediate BSA2, and BSA-K and BSA-L completely coincide; the prior literature does not clearly report a method for accurately detecting and separating the 14 related substances by using the same chromatographic condition.
Disclosure of Invention
Aiming at the defects in the prior art, the technical problem to be solved by the invention is how to construct a chromatographic condition to simultaneously and accurately analyze and detect the 14 related substances in the cisatracurium besilate bulk drug, wherein the structural formula of each related substance is as follows:
Figure BDA0003041553810000011
Figure BDA0003041553810000021
Figure BDA0003041553810000031
the inventor of the application optimizes the conditions of the composition of buffer salt, the selection of a pH regulator, the pH value of a solution, a gradient elution program and the like, gives consideration to the requirement of separating 14 related substances from the cisatracurium besilate in the raw material medicine of the cisatracurium besilate, finally establishes a proper analysis method, and can achieve baseline separation between the main component and each related substance and between each related substance, thereby achieving the purpose of the invention.
The technical scheme provided by the invention is as follows:
a method for detecting related substances in cisatracurium besilate bulk drugs is characterized in that a high performance liquid chromatography is adopted, and the chromatographic conditions comprise: the method comprises the steps of carrying out gradient elution by adopting a mixed solution of a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution of potassium dihydrogen phosphate buffer solution-methanol-acetonitrile, the mobile phase B is a mixed solution of potassium dihydrogen phosphate buffer solution-methanol-acetonitrile, the detection method realizes qualitative and quantitative detection on 14 impurities through one-time sample injection, the separation degree of a cisatracurium besilate peak and an adjacent impurity peak is not less than 1.5, and the separation degree between the impurity peaks is not less than 1.5.
In a preferred embodiment, the octadecylsilane bonded silica gel column is Agilent Zorbax SB-C18.6 mm X250mm, 3.5 μm.
In a preferred embodiment, the mobile phase A is potassium dihydrogen phosphate buffer solution-methanol-acetonitrile (75: 5: 20); the mobile phase B is potassium dihydrogen phosphate buffer solution-methanol-acetonitrile (50: 30: 20); the concentration of the buffer salt is 8.0-12.0 g of potassium dihydrogen phosphate in each 1000ml of the buffer salt solution.
In a preferred embodiment, the buffered salt solution has a pH of 3.8 to 4.2.
In a preferred embodiment, the buffered saline solution is adjusted to pH using a phosphoric acid solution.
In a preferred embodiment, the procedure of the gradient elution is: (1) The initial volume ratio of mobile phase A to mobile phase B was 80: 20; the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80: 20 to 40: 60 at a constant speed within 5-15 minutes; (2) The volume ratio of the mobile phase A to the mobile phase B is gradually changed from 40: 60 to 0: 100 at a constant speed within 25-30 minutes; (3) The volume of the mobile phase A and the mobile phase B is gradually changed from 0: 100 to 80: 20 at a constant speed within 45-45.01 minutes; (4) The volume ratio of the mobile phase A to the mobile phase B is kept constant at 80: 20 within 45.01-55 minutes.
In a preferred embodiment, the flow rate is 0.9 to 1.1ml/min, and the detection wavelength is 275 to 285nm; the column temperature is 40-50 ℃.
In a preferred embodiment, the sample volume is 20. Mu.l.
The method for measuring the related substances in the cisatracurium besilate raw material medicine by HPLC separation can adopt a self-contrast method to calculate the content of the related substances in the cisatracurium besilate raw material medicine.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the method for accurately detecting and separating the 14 related substances by adopting the same chromatographic condition has strong specificity, good reproducibility and high accuracy.
Drawings
FIG. 1 is a chromatogram of a blank solution from the specificity test of example 1;
FIG. 2 is a chromatogram of a system suitability solution for the specificity test of example 1;
FIG. 3 is a chromatogram of a test solution for the specificity test of example 1.
Detailed Description
In order that those skilled in the art may better understand the present invention, the following embodiments further illustrate the present invention. It should be understood that the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein. Wherein the cisatracurium besilate raw material drug comes from the pharmaceutical industry Co., ltd of the Guike of Lianhong, and the batch number is as follows: 002190301 at 99.4%.
The reagents used in the analysis method provided by the invention all meet the requirements of the analysis reagents of the 2020 edition of Chinese pharmacopoeia.
Example 1: specificity test
Chromatographic conditions are as follows:
the instrument comprises: a Thermo Ultimate3000 high performance liquid chromatograph;
a chromatographic column: agilent Zorbax SB C18 (4.6 mm. Times.250mm, 3.5 μm);
a detector: a UV detector with a detection wavelength of 280nm;
flow rate: 1.0ml/min;
column temperature: 45 ℃;
buffer salt: 1.02% monopotassium phosphate buffer (pH adjusted to 4.0 with phosphoric acid);
mobile phase A: phosphate buffer-methanol-acetonitrile (75: 5: 20);
and (3) mobile phase B: phosphate buffer-methanol-acetonitrile (50: 30: 20);
the proportions of mobile phase a and mobile phase B were set according to table 1.
The test steps are as follows:
diluting liquid: water-methanol-acetonitrile-formic acid (600: 200: 0.4);
system applicability solution: the cisatracurium besylate drug substance and the appropriate amounts of BSA2, BSA-B, BSA-C, BSA-D, BSA-E, BSA-F, BSA-G, BSA-H, BSA-U, BSA-L, BSA-J, BSA-M, BSA-I and BSA-K for each control were weighed precisely, placed in the same measuring flask, and diluted with an appropriate amount of a water-methanol-acetonitrile-formic acid (600: 200: 0.4) solution to give a solution containing cisatracurium besylate 0.7mg, BSA-B1.4. Mu.g, BSA-C1.4. Mu.g, BSA-D4.2. Mu.g, BSA-E2.8. Mu.g, BSA-F3.5. Mu.g, BSA-G1.4. Mu.g, BSA-H5. Mu.6. Mu.g, BSA-U0.7. Mu.g, BSA-I3.5. Mu.g, BSA-J3.5. Mu.g, BSA-K4.9. Mu.g, BSA-2.8. Mu.L, BSA-H5. Mu.7. Mu.g, BSA-7. Mu.g, BSA-U0.7. Mu.7. Mu.g, and BSA-K for each 1ml of BSA-M, and a suitable solution for the BSA-K for the system.
Test solution: taking about 35mg of cisatracurium besilate raw material medicine, precisely weighing, placing in a 50ml measuring flask, adding water-methanol-acetonitrile-formic acid (600: 200: 0.4) solution to dissolve and dilute to scale, shaking up to obtain a sample solution.
Respectively and precisely measuring 20 μ l of blank solution, system applicability solution and sample solution, performing sample injection detection under the above chromatographic conditions, and recording chromatogram. Blank pattern is shown in figure 1, system applicability solution pattern is shown in figure 2, and test solution pattern is shown in figure 3. System suitability solution results are shown in table 2.
Table 1 shows the ratio of mobile phases A and B in example 1
Time (minutes) Mobile phase A (%) Mobile phase B (%)
0 80 20
5 80 20
15 40 60
25 40 60
30 0 100
45 0 100
45.01 80 20
55 80 20
Table 2 shows the results of the solution for the system of example 1
Figure BDA0003041553810000051
Figure BDA0003041553810000061
Example 2: durability test
This example investigates the robustness of the chromatographic method by varying the parameters of part of the chromatographic conditions, based on the chromatographic conditions:
chromatographic conditions are as follows:
the instrument comprises the following steps: a Thermo Ultimate3000 high performance liquid chromatograph;
a chromatographic column: agilent Zorbax SB C18 (4.6 mm. Times.250mm, 3.5 μm);
a detector: a UV detector with a detection wavelength of 280nm;
flow rate: 1.0ml/min;
column temperature: 45 ℃;
buffer salt: 1.02% potassium dihydrogen phosphate buffer solution (pH adjusted to 4.0 with phosphoric acid);
mobile phase A: phosphate buffer-methanol-acetonitrile (75: 5: 20);
and (3) mobile phase B: phosphate buffer-methanol-acetonitrile (50: 30: 20);
the ratio of mobile phase a and mobile phase B was set according to table 1.
The testing steps are as follows:
diluting liquid: water-methanol-acetonitrile-formic acid (600: 200: 0.4);
the influence of changing chromatographic conditions such as flow rate, chromatographic column temperature, pH value of buffer solution, initial proportion of mobile phase or detection wavelength on the detection of the test solution is examined in a single-factor change mode, and the influence of changing chromatographic conditions on the detection result of each related substance in the test solution is mainly examined.
Test solution: taking about 35mg of cisatracurium besilate raw material medicine, accurately weighing, placing in a 50ml measuring flask, adding water-methanol-acetonitrile-formic acid (600: 200: 0.4) solution to dissolve and dilute to a scale, and shaking up to obtain a test solution.
Under the condition of each chromatogram, respectively and precisely measuring 20 mu l of test solution, and recording the chromatogram. The results of detection between the respective substances in the test solution are shown in Table 3.
Table 3 shows the results of the tests of example 2 for durability
Figure BDA0003041553810000062
Figure BDA0003041553810000071
In summary, the test results and the maps 1 to 3 of the example 1 show that, when the method provided by the invention is used for detecting the related substances of the cisatracurium besilate bulk drug, particularly BSA2, BSA-B, BSA-C, BSA-D, BSA-E, BSA-F, BSA-G, BSA-H, BSA-U, BSA-L, BSA-J, BSA-M, BSA-I and BSA-K, the blank is free of interference and has good specificity, the separation degree of the main peak and each related substance peak is more than 1.6, and the separation degree of each related substance is more than 1.9.
The test result of example 2 shows that the method is still suitable for detecting the related substances of the cisatracurium besilate bulk drug under the condition that the parameters of partial chromatographic conditions are changed by a single factor, wherein the influence of the detection result among the related substances in the tested sample solution is small, the method has good durability, and the purpose of realizing analysis by the method is not influenced at all by changing the chromatographic conditions within a proper range.
Therefore, the analysis method provided by the invention has the advantages of strong specificity, good reproducibility, high accuracy and the like in the determination of related substances in the cisatracurium besilate bulk drug.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such substitutions and modifications which are obvious to those skilled in the art are deemed to be within the scope of the present invention as claimed.

Claims (8)

1. A method for detecting related substances in cisatracurium besilate bulk drugs is characterized in that a high performance liquid chromatography is adopted, and the chromatographic conditions comprise: the method comprises the steps of carrying out gradient elution by adopting a mixed solution of a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution of potassium dihydrogen phosphate buffer solution-methanol-acetonitrile, the mobile phase B is a mixed solution of potassium dihydrogen phosphate buffer solution-methanol-acetonitrile, the detection method realizes qualitative and quantitative detection on 14 impurities through one-time sample injection, the separation degree of a cisatracurium besilate peak and an adjacent impurity peak is not less than 1.5, and the separation degree between the impurity peaks is not less than 1.5.
2. The detection method according to claim 1, wherein the octadecylsilane bonded silica gel column Agilent Zorbax SB-C184.6mm. Times.250mm, 3.5 μm.
3. The method for analyzing related substances in cisatracurium besilate according to claim 1, wherein the mobile phase a is potassium dihydrogen phosphate buffer-methanol-acetonitrile (75: 5: 20); the mobile phase B is potassium dihydrogen phosphate buffer solution-methanol-acetonitrile (50: 30: 20); the concentration of the buffer salt is 8.0-12.0 g of potassium dihydrogen phosphate in each 1000ml of the buffer salt solution.
4. The method for analyzing related substances in cisatracurium besilate according to claim 3, wherein the pH value of the buffered salt solution is 3.8-4.2.
5. The method for analyzing related substances in cisatracurium besilate according to claim 4, characterized in that the buffered salt solution is adjusted in pH value with phosphoric acid solution.
6. The method for detecting related substances in cisatracurium besilate according to claim 1, wherein the gradient elution procedure comprises: (1) The initial volume ratio of mobile phase A to mobile phase B was 80: 20; the volume ratio of the mobile phase A to the mobile phase B is gradually changed from 80: 20 to 40: 60 at a constant speed within 5-15 minutes; (2) The volume ratio of the mobile phase A to the mobile phase B is gradually changed from 40: 60 to 0: 100 at a constant speed within 25-30 minutes; (3) The volume of the mobile phase A and the mobile phase B is gradually changed from 0: 100 to 80: 20 at a constant speed within 45-45.01 minutes; (4) The volume ratio of the mobile phase A to the mobile phase B is kept constant at 80: 20 within 45.01-55 minutes.
7. The method for detecting related substances in cisatracurium besilate according to claim 1, characterized in that the flow rate is 0.9-1.1 ml/min, and the detection wavelength is 275-285 nm; the column temperature is 40-50 ℃.
8. The method for detecting related substances in cisatracurium besilate according to claim 1, characterized in that the sample injection volume is 20 μ l.
CN202110463028.9A 2021-04-27 2021-04-27 HPLC analysis detection method for related substances in cisatracurium besilate bulk drug Pending CN115248260A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116429940A (en) * 2023-04-14 2023-07-14 江苏原创药物研发有限公司 Method for detecting acrylic acid, methyl acrylate and ethyl acrylate in atracurium besilate bulk drug

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116429940A (en) * 2023-04-14 2023-07-14 江苏原创药物研发有限公司 Method for detecting acrylic acid, methyl acrylate and ethyl acrylate in atracurium besilate bulk drug

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