CN117907506A - Ultra-high performance liquid chromatography detection method for atosiban acetate impurity - Google Patents
Ultra-high performance liquid chromatography detection method for atosiban acetate impurity Download PDFInfo
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- CN117907506A CN117907506A CN202311821089.3A CN202311821089A CN117907506A CN 117907506 A CN117907506 A CN 117907506A CN 202311821089 A CN202311821089 A CN 202311821089A CN 117907506 A CN117907506 A CN 117907506A
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- G—PHYSICS
- G01—MEASURING; TESTING
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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
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Abstract
The invention relates to a liquid chromatography detection method of polypeptide impurities, belonging to the technical field of pharmaceutical chemistry. The invention provides an ultra-high performance liquid chromatography detection method for atosiban acetate impurities, which comprises the following steps: the method comprises the steps of taking a mixed solution of an organic reagent A, acid and water as a mobile phase A, taking a mixed solution of an organic reagent B, the organic reagent A, the acid and water as a mobile phase B, taking a C18 chromatographic column as a stationary phase, taking a detector as an ultraviolet detector, and adopting an ultra-high performance liquid chromatography gradient to elute polypeptide impurities. The method can effectively detect the impurities which are difficult to separate and are easy to generate during the process production and storage in the atosiban acetate, and can be used as an orthogonal method for detecting related substances of the atosiban acetate.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to an ultra-high performance liquid chromatography detection method for atosiban acetate impurities and application thereof.
Background
The synthetic polypeptide medicine has complex impurity spectrum and contains impurities introduced by protecting amino acid, initial material and reactant, impurities produced during technological process, degradation produced during storage and transportation, etc. In order to achieve effective detection of each potential impurity, detection methods employing a variety of different principles are generally required, such as reverse phase HPLC, ion exchange HPLC, size exclusion HPLC, and the like. The polypeptide impurities mainly comprise diastereoisomers, missing peptides, inserted peptides, broken peptides, bad peptides, substituted peptides, side chain groups modified, disulfide bond modified, deamidated impurities, amino acetylation and other impurities, and due to the complexity of the polypeptide impurities, a new impurity is generated when a certain amino acid is changed, theoretical impurities are many, and the difference between the impurity and a main component is small. For polypeptides with a high number of amino acids, it is difficult to control all impurities by one method, and certain special impurities need to be controlled by a special method.
Atosiban acetate is a disulfide-bonded cyclic polypeptide consisting of 9 amino acids, and exists in the form of acetate in medicines, and is commonly named as atosiban acetate. Atosiban acetate injection was first developed by the Ferring company, was first marketed in europe in 2000, and entered the chinese market in 2006. Atosiban acetate is a synthetic polypeptide, and due to the fact that the reaction steps, the feeding quantity and the like are large in the synthetic process, the synthetic impurity species are large, in addition, degradation impurities generated in the production and transportation processes are also large, part of the impurities are very similar to the atosiban main component in structure, the impurities are easy to generate and difficult to separate in the production, storage and transportation processes, the safety and the effectiveness of medicines are seriously affected, and if the control is not good, serious toxic and side effects are possibly generated. Therefore, an analysis method which is safe and reliable and can effectively detect and separate atosiban acetate raw material and preparation impurities simultaneously is developed, the product quality can be ensured, and the analysis method has great clinical value.
The prior art discloses the following technical scheme:
CN101696959B discloses a method for measuring the content of atosiban acetate and its preparation and the related substances. However, acetonitrile is selected as mobile phase B in this patent, and the highest gradient thereof is only 40%, and impurities with large polarity, particularly those involved in the present invention, cannot be separated.
CN109142580a discloses a method for determining atosiban acetate related substances, which also cannot separate impurities with large polarity and the impurities according to the present invention.
CN105949283a discloses atosiban acetate impurities, preparation and detection methods, but cannot separate impurities with polarity similar to that of the main component.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide an ultra-high performance liquid chromatography detection method for atosiban acetate impurities, and the method provides a special impurity separation method for separating impurities co-eluted with main components under a common acidic system aiming at the structural characteristics of the atosiban acetate impurities.
The invention also provides application of the detection method.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
The invention relates to an ultra-high performance liquid chromatography detection method for atosiban acetate impurities, which is characterized by comprising the following steps of: the method takes a mixed solution of an organic reagent, acid and water as a mobile phase, a C18 chromatographic column as a stationary phase, a detector as an ultraviolet detector, and an ultra-high performance liquid chromatography gradient elution of polypeptide impurities; the impurity is selected from at least one of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution comprising an organic reagent A, acid and water; the mobile phase B is a mixed solution comprising an organic reagent A, an organic reagent B, an acid and water.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the acid is at least one selected from phosphoric acid, trifluoroacetic acid, formic acid, acetic acid and boric acid; at least one of phosphoric acid and trifluoroacetic acid is preferable.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the organic reagent A is at least one selected from acetonitrile, methanol, ethanol and isopropanol; methanol is preferred.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the organic reagent B is at least one of acetonitrile, methanol, ethanol and isopropanol; acetonitrile is preferred.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the volume ratio of the organic reagent A, the acid and the water in the mobile phase A is 100:2:900 to 300:6:700; preferably, the volume ratio of the organic reagent A, the acid and the water in the mobile phase A is 200:4:800.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the volume ratio of methanol, phosphoric acid, trifluoroacetic acid and water in the mobile phase A is 100:1:1:900 to 300:3:3:700; preferably, the volume ratio of methanol, phosphoric acid, trifluoroacetic acid and water in the mobile phase A is 200:1.5:2.5:800.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the volume ratio of the organic reagent B, the organic reagent A, the acid and the water in the mobile phase B is 400:300:1:300 to 200:400:6:400; preferably, the volume ratio of the organic reagent B, the organic reagent A, the acid and the water in the mobile phase B is 400:300:4:300.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: acetonitrile, methanol, phosphoric acid, trifluoroacetic acid and water in the mobile phase B are in a volume ratio of 400:300:0.5:0.5:300 to 200:400:3:3:400; preferably, the volume ratio of acetonitrile, methanol, phosphoric acid, trifluoroacetic acid and water in the mobile phase B is 400:300:1.5:2.5:300.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the gradient of the mobile phase B ranges from 20% to 100%, preferably from 32% to 100%;
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the column temperature during the gradient elution is 20-60 ℃, preferably 50 ℃.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the flow rate during the gradient elution is 0.1-0.3mL/min, preferably 0.1mL/min.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the chromatographic column is a C18 chromatographic column.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the packed particle size of the column is 1.7 μm to 5. Mu.m, preferably 1.7. Mu.m.
Further, in the ultra performance liquid chromatography detection method disclosed by the invention, the following steps are adopted: the wavelength of the ultraviolet detector is 220nm.
The invention also provides an application of the detection method in detecting atosiban acetate raw material or preparation impurities; in the application, the impurity is selected from D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban, and the structural formula of the impurity is shown in the table below:
compared with the prior art, the invention has the following beneficial effects:
The method can effectively detect the impurities which are difficult to separate in the atosiban acetate (D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban), the impurities are easy to produce and difficult to separate during production, storage and transportation, the safety and the effectiveness of the medicine are seriously affected, the impurities can be simultaneously detected by separation, and the content of the impurities is monitored and controlled during the technological process or the storage and transportation, so that the quality of the atosiban acetate medicine is ensured. The method can be used as an orthogonal method for detecting related substances of the atosiban acetate bulk drug, can also be used as an orthogonal method of a main method of related preparations (such as atosiban acetate injection), and has good application prospect.
Drawings
Fig. 1: example 1 using this method, a resolution chromatogram comprising D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban, and Endo- [ beta-Ala 6 ] -atosiban 6 impurities was examined;
fig. 2: example 2 using this method, a resolution chromatogram comprising D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban, and Endo- [ beta-Ala 6 ] -atosiban 6 impurities was examined;
Fig. 3: example 3 using this method, a resolution chromatogram comprising D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban, and Endo- [ beta-Ala 6 ] -atosiban 6 impurities was examined;
Fig. 4: example 4 isolation chromatograms containing D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban 6 impurities were examined using the present method.
Detailed Description
The following detailed description of the present invention will be made in order to make the above-mentioned objects, features and advantages of the present invention more obvious, but the present invention is not limited thereto.
Example 1, an ultra performance liquid chromatography detection method of atosiban acetate impurity, one:
the method adopts ultra-high performance liquid chromatography gradient elution of polypeptide impurities.
The chromatographic column is a C18 reversed phase chromatographic column;
The packed particle size of the chromatographic column is 1.7 μm;
The volume ratio of the mobile phase A is methanol: trifluoroacetic acid: water = 240ml:0.5ml:760ml;
the volume ratio of the mobile phase B is acetonitrile: methanol: trifluoroacetic acid: water = 550ml:150ml:0.5ml:300ml;
the gradient range of the mobile phase B is 25% -47%;
The column temperature is 60 ℃ and the flow rate is 0.1mL/min in the gradient elution process;
the wavelength of the ultraviolet detector is 220nm.
Sample: isolation solution (containing atosiban: 0.6mg/ml, D- [ Ile3] -atosiban: 0.6. Mu.g/ml, D- [ Orn 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ Gly 9 ] -atosiban: 0.6. Mu.g/ml, [ delta-Ava 7 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 6 ] -atosiban: 0.6. Mu.g/ml)
The ultra-high performance liquid chromatography detection method of the atosiban acetate impurity is applied to detection and identification of polypeptide impurities generated in the production or storage process of the atosiban acetate bulk drug or preparation. The impurity is selected from the group consisting of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
Example 2, an ultra performance liquid chromatography detection method two for atosiban acetate impurity:
the method adopts ultra-high performance liquid chromatography gradient elution of polypeptide impurities.
The chromatographic column is a C18 reversed phase chromatographic column;
The packed particle size of the chromatographic column is 1.7 μm;
The volume ratio of the mobile phase A is methanol: trifluoroacetic acid: water = 200ml:1ml:800ml;
The volume ratio of the mobile phase B is acetonitrile: methanol: trifluoroacetic acid: water = 360ml:200ml:0.8ml:240ml;
the gradient range of the mobile phase B is 25% -47%;
the column temperature is 50 ℃ and the flow rate is 0.1mL/min in the gradient elution process;
the wavelength of the ultraviolet detector is 220nm.
Sample: isolation solution (containing atosiban: 0.6mg/ml, D- [ Ile3] -atosiban: 0.6. Mu.g/ml, D- [ Orn 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ Gly 9 ] -atosiban: 0.6. Mu.g/ml, [ delta-Ava 7 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 6 ] -atosiban: 0.6. Mu.g/ml)
The ultra-high performance liquid chromatography detection method of the atosiban acetate impurity is applied to detection and identification of polypeptide impurities generated in the production or storage process of the atosiban acetate bulk drug or preparation. The impurity is selected from the group consisting of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
Example 3, an ultra performance liquid chromatography detection method three of atosiban acetate impurity:
the method adopts ultra-high performance liquid chromatography gradient elution of polypeptide impurities.
The chromatographic column is a C18 reversed phase chromatographic column;
The packed particle size of the chromatographic column is 1.7 μm;
The volume ratio of the mobile phase A is methanol: trifluoroacetic acid: phosphoric acid: water = 160:2:2:640, a base;
the volume ratio of the mobile phase B is acetonitrile: methanol: trifluoroacetic acid: phosphoric acid: water = 320:240:2:2:240, a step of;
the gradient range of the mobile phase B is 32-60%;
the column temperature is 50 ℃ and the flow rate is 0.1mL/min in the gradient elution process;
the wavelength of the ultraviolet detector is 220nm.
Sample: isolation solution (containing atosiban: 0.6mg/ml, D- [ Ile3] -atosiban: 0.6. Mu.g/ml, D- [ Orn 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ Gly 9 ] -atosiban: 0.6. Mu.g/ml, [ delta-Ava 7 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 6 ] -atosiban: 0.6. Mu.g/ml)
The ultra-high performance liquid chromatography detection method of the atosiban acetate impurity is applied to detection and identification of polypeptide impurities generated in the production or storage process of the atosiban acetate bulk drug or preparation. The impurity is selected from the group consisting of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
Example 4, ultra performance liquid chromatography detection of atosiban acetate impurity four:
instrument: super high performance liquid chromatograph of Siemens flight Vanquish
Chromatographic column: c18 (2.1 mm x 150mm,1.7 μm);
Detection wavelength: 220nm;
Flow rate: 0.1ml/min;
column temperature: 50 ℃;
Sample: isolation solution (containing atosiban: 0.6mg/ml, D- [ Ile3] -atosiban: 0.6. Mu.g/ml, D- [ Orn 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ Gly 9 ] -atosiban: 0.6. Mu.g/ml, [ delta-Ava 7 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 8 ] -atosiban: 0.6. Mu.g/ml, endo- [ beta-Ala 6 ] -atosiban: 0.6. Mu.g/ml)
Sample injection amount: 1 μl;
mobile phase a: 200ml of methanol, 1.5ml of trifluoroacetic acid, 2.5ml of phosphoric acid and 800ml of water are taken, and the mixture is uniformly mixed, filtered and degassed to obtain the catalyst;
Mobile phase B: 400ml of acetonitrile, 300ml of methanol, 1.5ml of trifluoroacetic acid, 2.5ml of phosphoric acid and 300ml of water are taken, uniformly mixed, filtered and degassed to obtain the catalyst;
acquisition time: 70min
Elution conditions: table 1 below
TABLE 1 gradient elution
Separation effect: as shown in figure 1, the method can separate the impurities D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban from atosiban, and the separation degree of 6 impurities and a main component is more than 1.2, so that the separation effect is good; the detection limit of 6 impurities is 0.02%, and the sensitivity is good. See table 2:
TABLE 2 ultra high performance liquid chromatography detection results
Note that: "SPC074" is atosiban.
Claims (10)
1. An ultra-high performance liquid chromatography detection method for atosiban acetate impurity is characterized in that: the method takes a mixed solution of an organic reagent, acid and water as a mobile phase, a C18 chromatographic column as a stationary phase, a detector as an ultraviolet detector, and an ultra-high performance liquid chromatography gradient elution of polypeptide impurities; the impurity is selected from at least one of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
2. The method of claim 1, wherein: the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution composed of an organic reagent A, acid and water; the mobile phase B is a mixed solution composed of an organic reagent A, an organic reagent B, acid and water.
3. The detection method according to claim 2, wherein: the acid is at least one selected from phosphoric acid, trifluoroacetic acid, formic acid, acetic acid and boric acid.
4. The detection method according to claim 2, wherein: the organic reagent A is at least one selected from acetonitrile, methanol, ethanol and isopropanol; the organic reagent B is at least one of acetonitrile, methanol, ethanol and isopropanol; preferably, the organic reagent A is methanol and the organic reagent B is acetonitrile.
5. The detection method according to claim 2, wherein: the volume ratio of the organic reagent A, the acid and the water in the mobile phase A is 100:2:900 to 300:6:700; preferably, the volume ratio of the organic reagent A, the acid and the water in the mobile phase A is 200:4:800.
6. The detection method according to claim 2 or 4, characterized in that: the mobile phase A is prepared from methanol, phosphoric acid, trifluoroacetic acid and water according to the volume ratio of 100:1:1:900 to 300:3:3:700 parts; preferably, the volume ratio of methanol, phosphoric acid, trifluoroacetic acid and water in the mobile phase A is 200:1.5:2.5:800.
7. The detection method according to claim 2 or 4, characterized in that: the mobile phase B is prepared from an organic reagent B, an organic reagent A, acid and water according to the volume ratio of 400:300:1:300 to 200:400:6: 400; preferably, the volume ratio of the organic reagent B, the organic reagent A, the acid and the water in the mobile phase B is 400:300:4:300; or: the volume ratio of methanol, acetonitrile, phosphoric acid, trifluoroacetic acid and water in the mobile phase B is 400:300:0.5:0.5:300 to 200:400:3:3:400; preferably, the volume ratio of methanol, acetonitrile, phosphoric acid, trifluoroacetic acid and water in the mobile phase B is 400:300:1.5:2.5:300.
8. The detection method according to claim 2, wherein: the gradient of the mobile phase B ranges from 20% to 100%, preferably from 32% to 100%; the column temperature in the gradient elution process is 20-60 ℃, preferably 50 ℃; the flow rate during the gradient elution is 0.1-0.3mL/min, preferably 0.1mL/min.
9. The detection method according to claim 2, wherein: the gradient elution method comprises the following steps:
10. Use of the detection method according to any one of claims 1-9 for detecting atosiban acetate raw material or formulation impurities; the impurity is selected from at least one of D- [ Ile3] -atosiban, D- [ Orn 8 ] -atosiban, endo- [ Gly 9 ] -atosiban, [ delta-Ava 7 ] -atosiban, endo- [ beta-Ala 8 ] -atosiban and Endo- [ beta-Ala 6 ] -atosiban.
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