CN109142580A - Measure method of the atosiban acetate in relation to substance - Google Patents
Measure method of the atosiban acetate in relation to substance Download PDFInfo
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- CN109142580A CN109142580A CN201811063887.3A CN201811063887A CN109142580A CN 109142580 A CN109142580 A CN 109142580A CN 201811063887 A CN201811063887 A CN 201811063887A CN 109142580 A CN109142580 A CN 109142580A
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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
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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
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- G01N30/06—Preparation
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Abstract
The present invention relates to chemical analysis fields, in particular to a kind of measurement method of the atosiban acetate in relation to substance.Measure method of the atosiban acetate in relation to substance, it is then to be detected after Mobile phase B is eluted in acid mobile phase A and organic solvent using solution the following steps are included: globular preteins hydrophilic modifying silica gel is used to carry out loading for chromatographic column filler and to test solution.Wherein, mobile phase A and Mobile phase B are eluted with volume for the ratio of 60-90:10-40 when elution.It can quickly and efficiently separate and detect the related substance in atosiban acetate bulk pharmaceutical chemicals and injection.
Description
Technical field
The present invention relates to chemical analysis fields, in particular to a kind of measurement side of the atosiban acetate in relation to substance
Method.
Background technique
Atosiban is as current European drug general administration approval for treating unique palace with uterus specificity of premature labor
Contracting inhibitor, mechanism of action are and the ocytocin receptor on oxytocins competition mesometrium, decidua, fetal membrane, reduction oxytocins
The effect of, the calcium ion level on myocyte is reduced, to inhibit uterine contraction.Atosiban during production and storage,
Be also easy to produce impurity, and impurity easily causes allergic reaction, toxicity and other adverse reactions, but do not have in the prior art Dichlorodiphenyl Acetate Ah
The impurity of Tosi class analyzes and identifies method.
Summary of the invention
The present invention provides a kind of measurement method of the atosiban acetate in relation to substance, can quickly and efficiently separate simultaneously
Detect the related substance in atosiban acetate bulk pharmaceutical chemicals and injection.
The present invention is implemented as follows:
A method of the related substance of measurement atosiban acetate, comprising the following steps:
Globular preteins hydrophilic modifying silica gel is used to carry out loading for chromatographic column filler and to test solution, then using molten
Liquid is to be detected after Mobile phase B is eluted in acid mobile phase A and organic solvent；
Wherein, mobile phase A and Mobile phase B are eluted with volume for the ratio of 60-90:10-40 when elution.
The beneficial effects of the present invention are: measurement method of the atosiban acetate in relation to substance of the invention, selects spherical egg
White hydrophilic modifying silica gel and solution are that Mobile phase B is convenient for the related object of atosiban acetate with organic solvent in acid mobile phase A
The separation and elution of matter, sufficiently disclose the impurity of atosiban acetate, can quickly detect the related substance of atosiban acetate
Improve the safety of product, party's forensic science, reliable, the related substance of controllable atosiban acetate.
Detailed description of the invention
It in order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, below will be to institute in embodiment
Attached drawing to be used is needed to be briefly described.
Fig. 1 is the HPLC map of the standard items for the Atosiban containing known impurities that the embodiment of the present invention 1 provides；
Fig. 2 is the HPLC map for the test sample result that the embodiment of the present invention 1 provides；
Fig. 3 is the HPLC map for the test sample result that the embodiment of the present invention 2 provides；
Fig. 4 is the HPLC map for the test sample result that the embodiment of the present invention 3 provides；
Fig. 5 is the HPLC map for the test sample result that the embodiment of the present invention 4 provides；
Fig. 6 is the HPLC map for the test sample result that the embodiment of the present invention 5 provides；
Fig. 7 is that the detection of sensitivity test of the present invention limits chromatogram.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The measurement atosiban acetate of the embodiment of the present invention is specifically described in relation to the method for substance below.
The molecular weight of atosiban acetate is 994.19, during atosiban acetate produces or stores, by
Illumination, temperature, humidity or soda acid etc. influence, so that polymerization reaction occurs for atosiban acetate, obtain dimer or poly
Body, but the obtained specific structure of polymer can not determine, can not also determine the molecular weight of polymer or the kind of polymer
Class is unfavorable for the identification of atosiban acetate.Therefore, the present invention provides measurement method of the atosiban acetate in relation to substance, can
Separation identification is carried out with effective Dichlorodiphenyl Acetate Atosiban.
A method of the related substance of measurement atosiban acetate, comprising the following steps:
S1, configuration test solution；
Sample to be tested is dissolved in test solution obtained in mixed solution, wherein the quality percentage of test solution
Number is 0.7-1.8mg/ml, it is preferable that is 1-1.5mg/ml.Test solution can be convenient in solution using above-mentioned mass percent
Each substance separation, convenient for the subsequent polymer and Atosiban for affording different molecular weight.
Further, sample to be tested is Atosiban by strong acid, Qiang Guang, highly basic, the strong degradation reaction of high-temperature heating generation
Homemade sample to be tested afterwards simulates the rotten process of Atosiban by the strong degradation reaction, then can be used for detecting and divide
From.
Mixed solution is prepared after mobile phase A and the Mobile phase B are mixed according to the ratio that volume ratio is 60-90:10-40
Obtained solution.Mixed solution is consistent with solvent when elution, can reduce solvent peak, excludes solvent peak and does to impurity detection
It disturbs.
S2, elution and detection；
Globular preteins hydrophilic modifying silica gel is used as chromatographic column filler and is filled with into chromatographic column, globular preteins are hydrophilic
Modified silica-gel is silica gel microball surface bond hydrophilic polymer and hydrophily glycol-based functional group, so that it is to different molecular
The high molecular polymer of amount has different adsorption effects, while with good stability.
Further, the molecular weight of the globular preteins hydrophilic modifying silica gel used is 1000-10000, due to acetic acid atropic
The molecular weight of western class is 994.19, the molecular weight of the dimer of Atosiban about 2000 or so, and Atosiban other are more
The molecular weight of polymers or macromolecule impurity is also between 3000-6000, and the molecular weight of some polymer can reach 10000, therefore
Using above-mentioned molecular weight globular preteins hydrophilic modifying silica gel can Dichlorodiphenyl Acetate Atosiban and its polymer carry out it is good
Separation has more specificity.If selecting the higher silica gel of other molecular weight, be unable to Dichlorodiphenyl Acetate Atosiban and its polymer into
The good separation of row, then influences detection effect.
It using solution in acid mobile phase A and organic solvent is that Mobile phase B is eluted after completion of the sample, when elution flows
Dynamic phase A and Mobile phase B are eluted with volume for the ratio of 60-90:10-40.In the range to the polymerization in Atosiban
Object and macromolecule impurity and the separating effect of Atosiban principal component are more preferable, are able to satisfy the requirement that separating degree is greater than 1.5, and each
The peak shape of ingredient is preferable, and number of theoretical plate is also high.To in Atosiban polymer and macromolecule impurity can obtain it is more effective
Control and detection.When mobile phase composition or ratio not in the above range, then the polymer in Atosiban and macromolecule are miscellaneous
Matter is not completely separated with Atosiban, and the peak shape of each ingredient is poor, and number of theoretical plate is lower.Effectively it can not control and detect
Its polymer.
Further, mobile phase A is strong base-weak acid salt that pH is 2.0-5.0 or incomplete ionization in aqueous solution
Acid.
Further, strong base-weak acid salt is strong base weak acid salt buffer solution；
It is preferred that 0.01-1mol/ml phosphate buffer or 0.01-1mol/ml Acetate Solution；
The acid of incomplete ionization is monoacid or polyacid in aqueous solution；
It is preferred that it is 1.0~5.0% glacial acetic acid or 0.01~2.0% trifluoroacetic acid that the monoacid, which is mass percent,
The polyacid is 0.01~2.0% phosphoric acid.
Using above-mentioned acid solution, baseline noise is small, is conducive to the detection of impurity.And utilize citric acid buffer salt or its
His solvent then be easy to cause base limit noise big as mobile phase A, is unfavorable for the detection of impurity.Meanwhile using above-mentioned acid solution
Fixed phase surface can be quickly infiltrated, then to separate well between each substance, each peak theoretical cam curve is higher.
Further, Mobile phase B be cyanogen class solvent or alcohols solvent,
It is preferred that the cyanogen class solvent is acetonitrile, the alcohols solvent is monoalcohol solvent, more preferably methanol or isopropyl
Alcohol.
When carrying out hybrid analysis using above-mentioned Mobile phase B and mobile phase A component, chromatographic system is easily easy balance, stability
Preferably, the pressure of chromatographic column is lower, the separation to polymer and macromolecule impurity and Atosiban principal component in Atosiban
Effect is more preferable, is able to satisfy the requirement that separating degree is greater than 1.5, and the peak shape of each ingredient is preferable, number of theoretical plate is also high.To atropic west
While capable of obtaining faster, effective control with detection of polymer and macromolecule impurity in class, additionally it is possible to protect
Chromatographic column extends the service life of chromatographic column.If will lead to chromatographic system using other organic solvents and be difficult to balance, very
There is certain selectivity to organic solvent to balance, especially chromatographic column itself is unable to reach, therefore has centainly to chromatographic column
Damage, thus methanol or acetonitrile or isopropanol is selected to be very important for Mobile phase B.
Further, in carrying out test process, the present invention is also additionally arranged guard column, using TSK-gel Guard
The packing technique of columm SWXL guard column, use is consistent with chromatographic column with detection, and guard column not only will not to sample detection
It has an impact, and when sample analysis amount is big, avoids hurting pillar, extend the service life of chromatographic column, ensure that the standard of detection data
While true property and reproducibility, the cost of chromatographic column loss is also reduced.
It is detected simultaneously using high-efficient liquid phase analysis, Detection wavelength 210-230nm.It is carried out using high-efficient liquid phase analysis
Flow velocity is 0.4-1.1ml/min when detection, and column temperature is 20~40 DEG C, and sample volume is 20 μ l.
S3, reference map；
Further, the structure of atosiban acetate interpolymer not can determine that, the information such as molecular weight can not determine,
Therefore the embodiment of the present invention is by setting reference map, convenient for being quickly found out the molecular weight of macromolecule impurity.
Specifically, before detecting to the test solution, the standard of the Atosiban containing known impurities is utilized
Product are analyzed, and are obtained referring to map；Detection operation and the present invention to the standard items of the Atosiban containing known impurities is real
It is consistent with the operation of S2 to apply a S1, then obtains referring to map.
The test map that then sample to be tested is detected is compared with referring to map, then determines test solution
The molecular weight of interpolymer.
Further, it is known that impurity includes multiple impurity, and the molecular weight of multiple impurity is 1500-6000.
Further, multiple impurity are any one in actrapid monotard, Thymosin alpha 1 and growth hormone release inhibiting hormone.Using upper
It states substance to be used as referring to impurity, more rapidly more easily the standard items of Atosiban can be detected, and be also more conducive to sentence
Determine the molecular weight of polymer.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
The present embodiment provides a kind of measurement method of the atosiban acetate in relation to substance, comprising the following steps:
Weigh atosiban acetate (atosiban acetate after having carried out strong degradation experiment), add mixed solution dissolve and it is dilute
The solution that the 1.0mg containing atosiban acetate in every 1ml is made is released, as test solution；Precision measurement test solution is appropriate,
The solution of the 10 μ g containing atosiban acetate in every 1ml is made of mixed solution dilution, as sample introduction solution.Sample introduction simultaneously records chromatography
Figure.
Actrapid monotard (molecular weight 5808) reference substance, Thymosin alpha 1 (molecular weight 3108) reference substance, growth hormone release inhibiting hormone are taken respectively
(molecular weight 1638) reference substance and atosiban acetate reference substance, respectively plus mixed solution dissolves and dilutes to be made in every lml and contains
Actrapid monotard, Thymosin alpha 1, growth hormone release inhibiting hormone are that the solution of 100 μ g/ml and Atosiban 1mg/ml is obtained containing known
The standard items of the Atosiban of impurity.
Wherein, the ratio of mobile phase A and Mobile phase B is 90:10 in mixed solution, and mobile phase A is that mass percent is
5.0% glacial acetic acid, Mobile phase B are acetonitrile.
Use globular preteins hydrophilic modifying silica gel for chromatographic column filler and be filled with into chromatographic column up to Tosoh
TSK-gel G2000SWXL chromatographic column, the molecular weight of the globular preteins hydrophilic modifying silica gel used then divide for 1000-10000
The standard items of the other Atosiban for containing known impurities to test solution carry out loading and elution.Wherein mobile phase A is quality
Percentage is 5.0% glacial acetic acid, and Mobile phase B is acetonitrile, and the ratio of mobile phase A and Mobile phase B is 90:10；Column temperature is 20~40
℃；Flow velocity: 1.0ml/min, sample volume are 20 μ l.Testing result is referring to Fig. 1 and Fig. 2.
It meanwhile when detecting, is guard column, the packing technique of use using TSK-gel Guard columm SWXL column
It is consistent with detection chromatographic column.
According to Fig. 1 and Fig. 2 it is found that polymer and macromolecule impurity appearance before Atosiban peak, and can
Reach baseline separation with Atosiban main peak, specificity is strong.Meanwhile comparison diagram 1 and Fig. 2 are it is found that the molecular weight of polymer is general
It is 2000.
Embodiment 2-5
The operation of method and embodiment 1 of the measurement atosiban acetate in relation to substance that embodiment 2-5 is provided is almost the same,
Difference is that operating condition changes.
Embodiment 2: chromatographic condition: the mass percent of test solution is 1.5mg/ml, mobile phase A and Mobile phase B
Volume ratio is 80:20, and mobile phase A is the 1mol/ml phosphate solution that pH is 2.0, and Mobile phase B is methanol, flow velocity 1.1ml/
Min, column temperature are 21~37 DEG C；Detection wavelength is 225nm.
Embodiment 3: chromatographic condition: the mass percent of test solution is 1.8mg/ml, mobile phase A and Mobile phase B
Volume ratio is 60:40, and mobile phase A is 2.0% phosphoric acid, and Mobile phase B is isopropanol, and flow velocity 0.5ml/min, column temperature is 30~39
℃；Detection wavelength is 230nm.
Embodiment 4: chromatographic condition: the mass percent of test solution is 0.7mg/ml, mobile phase A and Mobile phase B
Volume ratio is 75:25, and mobile phase A is the 0.01mol/ml acetate buffer that pH is 5.0, and Mobile phase B is methanol, and flow velocity is
0.8ml/min, column temperature are 22~29 DEG C；Detection wavelength is 215nm.
Embodiment 5: chromatographic condition: the mass percent of test solution is 1.0mg/ml, mobile phase A and Mobile phase B
Volume ratio is 70:30, and mobile phase A is 0.01% trifluoroacetic acid, and Mobile phase B is acetonitrile, flow velocity 0.4ml/min, column temperature 28
~30 DEG C；Detection wavelength is 220nm.
The test map of embodiment 2- embodiment 5 referring to Fig. 3-6, comparison diagram 3 and Fig. 1 it is found that the molecular weight of polymer about
Be 2000, comparison diagram 4 and Fig. 1 it is found that the molecular weight of polymer is about 4000, comparison diagram 5 and Fig. 1 it is found that polymer molecule
Amount about 4500, comparison diagram 6 and Fig. 1 are it is found that the molecular weight of polymer is about 2000.
Sensitivity test
After mixed solution dilution is added in sample to be tested, 20 μ l is taken to inject liquid chromatograph, record chromatogram, until main peak
Peak height is 10 times of baseline noise, and then measuring quantitative limit is about 2ng, as a result referring to Fig. 7.
Test sample concentration provided in an embodiment of the present invention is 1.0mg/mL, is quantitatively limited to 0.05 μ g/ml, and quantitative limit about supplies
The 0.005% of test product concentration, below reporting limit 0.05%, impurity sensitivity is higher, illustrates chromatostrip provided by the invention
Part sensitivity with higher.
In conclusion measurement method of the atosiban acetate in relation to substance of the invention, selects globular preteins hydrophilic modifying
Silica gel and solution in acid mobile phase A and organic solvent be Mobile phase B convenient for separation of the atosiban acetate in relation to substance and
Elution, sufficiently discloses the impurity of atosiban acetate, can quickly detect the related substance of atosiban acetate and improve product
Safety, party's forensic science, reliable, the related substance of controllable atosiban acetate.
The foregoing is merely the preferred embodiment of the present invention, are not intended to restrict the invention, for this field
For technical staff, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any
Modification, equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of measurement method of the atosiban acetate in relation to substance, which comprises the following steps:
It uses globular preteins hydrophilic modifying silica gel to carry out loading for chromatographic column filler and to test solution, is then in using solution
Acid mobile phase A and organic solvent is to be detected after Mobile phase B is eluted；
Wherein, mobile phase A and Mobile phase B are eluted with volume for the ratio of 60-90:10-40 when elution.
2. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that the mobile phase
A is the strong base-weak acid salt that pH is 2.0-5.0 or the acid of incomplete ionization in aqueous solution.
3. measurement method of the atosiban acetate in relation to substance according to claim 2, which is characterized in that the highly basic is weak
Hydrochlorate is strong base weak acid salt buffer solution；
It is preferred that 0.01-1mol/ml phosphate buffer or 0.01-1mol/ml Acetate Solution；
The acid of incomplete ionization is monoacid or polyacid in aqueous solution；
It is preferred that it is 1.0~5.0% glacial acetic acid or 0.01~2.0% trifluoroacetic acid that the monoacid, which is mass percent, it is described
Polyacid is 0.01~2.0% phosphoric acid.
4. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that the mobile phase
B be cyanogen class solvent or alcohols solvent,
It is preferred that the cyanogen class solvent is acetonitrile, the alcohols solvent is monoalcohol solvent, more preferably methanol or isopropanol.
5. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that the confession
It before test sample solution is detected, is analyzed, is obtained referring to map using the standard items of the Atosiban containing known impurities；
After the completion of being detected to the test solution, obtained test map is compared with described referring to map, is judged
The molecular weight of the test solution interpolymer；Wherein, the known impurities include multiple impurity, and multiple impurity
Molecular weight is 1500-6000.
6. measurement method of the atosiban acetate in relation to substance according to claim 5, which is characterized in that multiple described miscellaneous
Matter is any one in actrapid monotard, Thymosin alpha 1 and growth hormone release inhibiting hormone.
7. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that the test sample
Solution is that sample to be tested is dissolved in solution obtained in mixed solution, it is preferable that the mixed solution is the mobile phase A and institute
State the solution being prepared after Mobile phase B mixing.
8. measurement method of the atosiban acetate in relation to substance according to claim 7, which is characterized in that the mixing is molten
The solution obtained after being mixed the ratio of mobile phase A and Mobile phase B with volume for 60-90:10-40 in liquid.
9. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that when being detected
Flow velocity is 0.4-1.1ml/min, and column temperature is 20~40 DEG C.
10. measurement method of the atosiban acetate in relation to substance according to claim 1, which is characterized in that detection is benefit
It is detected with high-efficient liquid phase analysis, Detection wavelength 210-230nm.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110218242A (en) * | 2019-06-26 | 2019-09-10 | 海南中和药业股份有限公司 | A kind of preparation method of atosiban acetate impurity |
| CN110658296A (en) * | 2019-10-30 | 2020-01-07 | 海南通用三洋药业有限公司 | Method for detecting high-molecular polymer in atosiban acetate injection |
| CN113702560A (en) * | 2021-08-31 | 2021-11-26 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting by-product generated in chemical synthesis of somatostatin |
| CN113720955A (en) * | 2021-08-31 | 2021-11-30 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting ganirelix acetate high-molecular polymer |
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| CN110218242A (en) * | 2019-06-26 | 2019-09-10 | 海南中和药业股份有限公司 | A kind of preparation method of atosiban acetate impurity |
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| CN113720955A (en) * | 2021-08-31 | 2021-11-30 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting ganirelix acetate high-molecular polymer |
| CN113702560B (en) * | 2021-08-31 | 2022-07-08 | 哈尔滨吉象隆生物技术有限公司 | Method for detecting by-product generated in chemical synthesis of somatostatin |
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