CN114252535A - Detection method of cisatracurium besilate related substances - Google Patents
Detection method of cisatracurium besilate related substances Download PDFInfo
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- CN114252535A CN114252535A CN202111573400.8A CN202111573400A CN114252535A CN 114252535 A CN114252535 A CN 114252535A CN 202111573400 A CN202111573400 A CN 202111573400A CN 114252535 A CN114252535 A CN 114252535A
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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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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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
- G01N30/26—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
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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
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
Abstract
The invention belongs to the field of pharmaceutical analysis, and relates to a detection method of cisatracurium besilate related substances, which specifically comprises the steps of detecting by using a high performance liquid chromatography, wherein a chromatographic column is a C18 column, a buffer solution with a pH value of 3.5-4.5 is used as a water phase, methanol or acetonitrile is used as an organic phase, gradient elution is carried out, and the detection wavelength is 190-320 nm. The detection method can effectively detect related substances in the cisatracurium besilate, has the advantages of high sensitivity, good separation degree, good repeatability and durability, simple operation and stable and reliable result, and can be used for controlling impurities in the cisatracurium besilate and providing effective guarantee for the quality of a final finished product.
Description
Technical Field
The invention relates to a detection method for impurities in a cisatracurium besilate raw material and an injection thereof, in particular to a method for detecting the cisatracurium besilate raw material and related substances in the injection thereof by using a high performance liquid chromatography, and belongs to the field of drug analysis.
Background
A neuromuscular blocker is a muscle relaxant that does not have a central role and acts to block synaptic signaling through interaction with acetylcholine receptors at neuromuscular junctions. The neuromuscular blocking drug can act before or after the neuromuscular junction, but only the neuromuscular blocking drug acting after the neuromuscular junction has clinical application value, can be used as an auxiliary drug for general anesthesia operation, and representative drugs include cisatracurium, rocuronium, vecuronium and the like.
Neuromuscular blockers are classified into depolarizations and non-depolarizations according to their mechanism of action, and short, medium and long-acting according to their duration of action. Succinylcholine is currently the only depolarizing drug. Non-depolarizing neuromuscular blockers hinder acetylcholine action as receptor competitive antagonists, and these are further divided into two groups: amino steroids (e.g., pancuronium bromide, vecuronium bromide, rocuronium bromide) and benzylisoquinolines (e.g., atracurium, docromine, micracromine, cis-atracurium).
Cisatracurium besilate is used as a non-polar neuromuscular blocking agent and is suitable for surgery and other procedures as well as intensive care therapy. The chemical name of the compound is (1R,1 ' R,2R,2 ' R) -2,2 ' - (3, 11-dioxo-4, 10-dioxotridecylmethylene) bis (1,2,3, 4-tetrahydro-6, 7-dimethoxy-2-methyl-1-veratryl isoquinolinium) diphenylsulfonate, the molecular weight is 1243.49, and the specific structural formula is shown as follows:
cisatracurium besilate injection was first developed by Aspen/GSK company and was marketed in the uk 8.7.1995 under the name of nimox; nimex, developed by Aspen corporation on 31/3/2018, was approved by the national drug administration to market in the chinese market. The cisatracurium besilate serving as a novel neuromuscular blocking agent not only has the relevant pharmacological characteristics of atracurium besilate, but also has the relevant advantage of small influence on the cardiovascular system. Cisatracurium besilate has greater muscle relaxation strength and fewer adverse drug reactions than atracurium besilate. Cisatracurium besilate has the obvious advantages of small influence on autonomic nerves, strong effect compared with other similar medicines, no accumulation effect after multiple times of administration, positive correlation between muscle relaxation strength and administration dosage, main dependence on Hofmann effect on metabolism, no muscle relaxation effect of metabolite, and capability of using larger dosage without worrying about histamine release and change of hemodynamics.
The standard of raw materials and injection of the cisatracurium besilate is collected in Chinese pharmacopoeia ChP2020 and United states pharmacopoeia USP43, and the standard of raw materials and injection of the cisatracurium besilate is collected in European pharmacopoeia EP10.0, so that related substances are controlled, and known impurities are also controlled. Known impurities controlled by Chinese pharmacopoeia comprise impurities f and g; known impurities controlled in the USP43 standard are impurities a, b, c, d, e, f, g, h, i, j, k, l; known impurities controlled in the european pharmacopoeia EP10.0 standard are impurities a, b, c, d, e, f, g, h, i, k, l, m, which originate from process impurities, intermediate products and degradation products.
In order to strictly require the quality of cis-atracurium besilate, known impurities a, b, c, d, e, f, g, h, i, j, k, l, m and unknown impurities are controlled, and at present, the detection means of the related substances in the cis-atracurium besilate sample needs to be improved.
Disclosure of Invention
According to the invention, the high performance liquid chromatography is adopted to detect related substances in the cis-atracurium besilate, so that all known impurities can be effectively detected, the complete separation of the cis-atracurium besilate and the known impurities is realized, the method can be used for quality control in the production of the cis-atracurium besilate raw material and injection thereof, and the quality of the cis-atracurium besilate is effectively controlled.
A method for detecting cisatracurium besilate related substances by using a high performance liquid chromatography is provided.
Step one, preparing a sample solution, wherein the sample solution is as follows: taking a proper amount of the cisatracurium besilate, precisely weighing, and in the actual detection process, replacing the cisatracurium besilate with a raw material for the cisatracurium besilate and an injection of the cisatracurium besilate. The mixture was dissolved in a solvent [ water-acetonitrile-methanol-formic acid (60: 20:20:0.04) ] and diluted to give a solution containing about 0.5mg of cisatracurium per 1 ml.
Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting with a solvent to obtain a solution containing about 0.5 μ g of atracurium per 1ml as a control solution.
And step two, injecting the sample and the reference solution obtained in the step one into a high performance liquid chromatograph, wherein a filler of a stationary phase of the chromatographic column is octadecylsilane chemically bonded silica, gradient elution is performed by adopting a mobile phase A and a mobile phase B, and detection is performed after elution.
The chromatographic conditions of the high performance liquid chromatography are as follows: the mobile phase of the high performance liquid chromatography comprises: the mobile phase A is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 3.5-4.5, methanol and acetonitrile in a volume ratio of 75:5:20, and a mobile phase B is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 3.5-4.5, methanol and acetonitrile in a volume ratio of 50:30:20, the column temperature of the high performance liquid chromatography is 30-50 ℃, the flow rate of the mobile phase is 0.5-1.5 mL/min, the detection wavelength is 190-320 nm, the stationary phase filler of the chromatographic column is octadecylsilane chemically bonded silica, and the mobile phase gradient elution conditions are as follows: the ratio of the mobile phase A to the mobile phase B is as follows in terms of volume ratio:
furthermore, the cisatracurium besilate is cisatracurium besilate raw material or cisatracurium besilate injection, and the chromatographic conditions of the high performance liquid chromatography are as follows:
the mobile phase of the high performance liquid chromatography comprises: the mobile phase A is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 4.0, methanol and acetonitrile according to a volume ratio of 75:5:20, and a mobile phase B is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 4.0, methanol and acetonitrile according to a volume ratio of 50:30:20, the column temperature of the high performance liquid chromatography is 45 ℃, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 280nm, the chromatographic column is an Agilent C18 column, and the mobile phase gradient elution conditions are as follows: the ratio of the mobile phase A to the mobile phase B is as follows in terms of volume ratio:
the buffer solution is phosphate buffer solution, wherein phosphate is selected from one of diamine hydrogen phosphate, ammonium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate and disodium hydrogen phosphate; preferably, the buffer solution is potassium dihydrogen phosphate.
According to an embodiment of the present invention, the related substance includes any one selected from impurities a, b, c, d, e, f, g, h, i, j, k, l, m and a combination of two or more thereof.
The method for detecting the cisatracurium besilate raw material and the related substances in the injection by using the high performance liquid chromatography can effectively detect the content of the related substances in the cisatracurium besilate, and has the advantages of high separation degree, good repeatability and durability, low detection limit, simple operation, and stable and reliable result, so that the method can be used for quality control of the cisatracurium besilate raw material and the injection, and provides effective guarantee for the quality of a final finished product.
Drawings
FIG. 1 structural formula of cisatracurium besylate
FIG. 2 structural formula of impurity a
FIG. 3 structural formula of impurity b
FIG. 4 structural formula of impurity c
FIG. 5 structural formula of impurity d
FIG. 6 structural formula of impurity e
FIG. 7 structural formula of impurity f
FIG. 8 structural formula of impurity g
FIG. 9 structural formula of impurity h
FIG. 10 structural formula of impurity i
FIG. 11 structural formula of impurity j
FIG. 12 structural formula of impurity k
FIG. 13 structural formula of impurity l
FIG. 14 structural formula of impurity m
FIG. 15 high performance liquid chromatography of blank solvent
FIG. 16 high performance liquid chromatography of blank excipients
FIG. 17 high performance liquid chromatography of cisatracurium besilate injection control solution
FIG. 18 high performance liquid chromatography of cisatracurium besilate injection sample solution
FIG. 19 is a high performance liquid chromatography of cisatracurium besilate injection sample solution with known impurities
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. The examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
Example (b):
a method for detecting substances related to cisatracurium besilate injection comprises the following steps:
step one, preparing a sample solution, wherein the sample solution is as follows: an appropriate amount of the product was weighed out and diluted with a solvent [ water-acetonitrile-methanol-formic acid (600:200:200:0.4) ] to prepare a solution containing about 0.5mg of cisatracurium per 1 ml.
Control solution: precisely measuring a proper amount of the test solution, and quantitatively diluting with a solvent to obtain a solution containing about 0.5 μ g of cisatracurium per 1ml as a control solution.
And step two, injecting the sample and the reference solution obtained in the step one into a high performance liquid chromatograph, wherein a filler of a stationary phase of the chromatographic column is octadecylsilane chemically bonded silica, gradient elution is performed by adopting a mobile phase A and a mobile phase B, and detection is performed after elution.
The mobile phase A is a mixed solution obtained by mixing potassium dihydrogen phosphate buffer solution with the pH value adjusted to 4.0, methanol and acetonitrile according to the volume ratio of 75:5: 20; the mobile phase B is a mixed solution obtained by mixing potassium dihydrogen phosphate buffer solution with the pH value adjusted to 4.0, methanol and acetonitrile according to the volume ratio of 50:30: 20.
The column temperature was 45 ℃.
The flow rate of the mobile phase was 1.0 mL/min.
The detection wavelength is 280 nm.
The chromatographic column is an Agilent C18 column.
The mobile phase gradient elution conditions are as follows: the ratio of the mobile phase A to the mobile phase B is as follows in terms of volume ratio:
system applicability solution: the separation degree of cis atracurium and each impurity peak is not less than 1.5.
Precisely measuring the sample solution and the control solution by 20 μ l each, injecting into a liquid chromatograph, and recording chromatogram. See fig. 15-19.
The mixed impurity solution has impurity a, b, c, d, e, f, g, main peak, m, k, i, l, h and j in the order of emergence, and the separation degree of each peak is not less than 1.5.
Claims (10)
1. A method for detecting cis atracurium besilate related substances is characterized in that the method is a high performance liquid chromatography method.
2. The method of claim 1, wherein the mobile phase of the high performance liquid chromatography comprises: the detection method comprises the following steps of (1) obtaining a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 3.5-4.5, methanol and acetonitrile according to a volume ratio of 75:5:20, the mobile phase B is a mixed solution obtained by mixing a buffer solution with a pH value adjusted to 3.5-4.5, methanol and acetonitrile according to a volume ratio of 50:30:20, and the detection wavelength is 190-320 nm; the high performance liquid chromatography adopts gradient elution.
3. The method of claim 1, wherein the mobile phase of the high performance liquid chromatography comprises: the mobile phase A is a mixed solution obtained by mixing a buffer solution with the pH value adjusted to 4.0, methanol and acetonitrile according to a volume ratio of 75:5:20, and the mobile phase B is a mixed solution obtained by mixing a buffer solution with the pH value adjusted to 4.0, methanol and acetonitrile according to a volume ratio of 50:30:20, and the detection wavelength is 280 nm; the high performance liquid chromatography adopts gradient elution.
4. The method of claim 1, wherein the buffer solution for high performance liquid chromatography is phosphate buffer solution, wherein the phosphate is selected from one of diamine hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, and disodium hydrogen phosphate; preferably, the buffer solution is potassium dihydrogen phosphate.
5. The method of claim 1, wherein the high performance liquid chromatography has a column temperature of 30 to 50 ℃, preferably 45 ℃.
6. The method according to claim 1, wherein the flow rate of the mobile phase of the high performance liquid chromatography is 0.5 to 1.5mL/min, preferably 1.0 mL/min.
7. The method of claim 1, wherein the high performance liquid chromatography is used for detection of a substance, including any one selected from the group consisting of impurities a, b, c, d, e, f, g, h, i, j, k, l, m, and combinations of two or more thereof.
8. The method of claim 1, wherein the column stationary phase packing of high performance liquid chromatography is octadecylsilane chemically bonded silica, preferably a C18 column.
9. The method of claim 1, wherein the C18 column is an Agilent C18 column.
10. The method of claim 1, wherein the cisatracurium besilate is a cisatracurium besilate stock or a cisatracurium besilate injection.
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Cited By (1)
| 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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2021
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Cited By (1)
| 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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