CN113030281A - Method for separating compound D and/or J - Google Patents

Method for separating compound D and/or J Download PDF

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CN113030281A
CN113030281A CN201911348372.2A CN201911348372A CN113030281A CN 113030281 A CN113030281 A CN 113030281A CN 201911348372 A CN201911348372 A CN 201911348372A CN 113030281 A CN113030281 A CN 113030281A
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impurity
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CN113030281B (en
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张�荣
周春燕
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Chongqing Huapont Pharm Co Ltd
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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
    • 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
    • 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
    • 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
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N2030/042—Standards
    • G01N2030/047—Standards external
    • 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
    • G01N2030/065—Preparation using different phases to separate parts of sample

Abstract

The invention belongs to the technical field of analytical chemistry, and particularly relates to a method for separating a compound D and/or a compound J. The compound D, J is an impurity D, J in a betamethasone dipropionate product, and a novel high performance liquid separation and identification method is established by screening chromatographic columns and chromatographic conditions. The method has high separation degree and high sensitivity; the specificity is strong; the reproducibility is good; the operation is simple and feasible.

Description

Method for separating compound D and/or J
Technical Field
The invention belongs to the technical field of analytical chemistry, and particularly relates to a method for separating a compound D and/or a compound J.
Background
Betamethasone dipropionate (betamethasone dipropionate), also known as betamethasone dipropionate, has a chemical name of 11 beta, 17 alpha, 21-trihydroxy-16 beta-methyl-9 alpha-fluoro-pregna-1, 4-diene-3, 20-dione-17, 21-dipropionate and is a prodrug of the glucocorticoid medicine betamethasone. Compared with the original medicine, the structure of the compound has two acrylate groups added, so that the compound has the advantages of higher lipid solubility, excellent skin permeability, long maintenance time and the like. The compound preparation Diprospan (Diprospan) formed by the compound preparation and betamethasone sodium phosphate has the effects of resisting inflammation, rheumatism and allergy, and is mainly used for treating allergic and autoimmune inflammatory diseases clinically, such as neurodermatitis, leucoderma, urticaria, rheumatoid arthritis, lupus erythematosus, scleroderma, acute leukemia and the like.
A plurality of impurities can be generated in the synthesis process of betamethasone dipropionate, the detection and analysis of the impurities are beneficial to the quality control of the betamethasone dipropionate product, wherein the impurities D and the impurities J cannot be effectively separated according to the existing EP10.0, USP42S1 and JP17 pharmacopoeia methods, so that the invention researches a method for effectively and stably separating the impurities D and the impurities J from the main components of the betamethasone dipropionate and other impurities.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for separating compound D and/or J, specifically impurities in a betamethasone dipropionate product, which is simple to operate, can well separate impurities D and impurities J of the betamethasone dipropionate product from other 10 known impurities and main components which may be present in the product within 23 minutes, and has a separation degree between the impurities D and the impurities J of more than 1.5.
In order to achieve the purpose, the invention adopts the following scheme:
the method for separating the compounds D and/or J adopts an HPLC method for separation, in the existing pharmacopeia method, EP10.0 has relatively good separation on related substances of the compounds, but impurities D and J cannot be well separated, so that the efficient and stable HPLC separation method is established by screening of HPLC conditions.
Further, in the chromatographic column adopted in the HPLC separation process, octadecyl bonded silica gel is used as a filler, tetrahydrofuran aqueous solution is used as a mobile phase A, and acetonitrile-tetrahydrofuran solution is used as a mobile phase B for elution, and the structural formula of the compound D, J is shown as a formula I and a formula II:
Figure BDA0002334016410000021
specifically, the method can separate the impurities D and/or J from the betamethasone dipropionate product from other impurities and main components, wherein the other impurities comprise A, B, C, E, F, G, I, p-toluenesulfonic acid, methyl p-toluenesulfonate and ethyl p-toluenesulfonate, and the structural formulas of the other impurities are shown as follows:
Figure BDA0002334016410000022
Figure BDA0002334016410000031
further, the separation degree of the separation impurity D is 1.82 to 2.02.
Further, the separation degree of the separated impurity J is 1.74 to 1.87.
Further, the concentration of the tetrahydrofuran aqueous solution is 8%, and the concentration of the tetrahydrofuran acetonitrile solution is 8%.
Specifically, the mobile phase A is water-tetrahydrofuran, the volume ratio of the water to the tetrahydrofuran is 920:80, the mobile phase B is acetonitrile-tetrahydrofuran, and the volume ratio of the acetonitrile to the tetrahydrofuran is 920: 80.
Further, carrying out linear gradient elution on the mobile phase A and the mobile phase B according to a certain proportion, wherein the gradient proportion is as follows:
0min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
10min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
10.1min, wherein the volume ratio of the mobile phase A to the mobile phase B is 20: 80;
15min, wherein the volume ratio of the mobile phase A to the mobile phase B is 20: 80;
15.1min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
and 23min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35.
Further, the flow rate of elution was 1.0 ml/min.
Further, the wavelength of detection is 220-280nm, preferably 254 nm.
Further, the column temperature of the column was 30 ℃.
The invention also aims to provide a method for identifying the compound D and/or J, which is accurate and effective in identification, can accurately judge the impurity D and/or J in the betamethasone dipropionate product and calculate the content of the impurity D and/or J.
In order to achieve the purpose, the invention adopts the following scheme:
the identification method is to separate the compounds D and/or J by the method of the first aim by taking the wavelength of a high performance liquid phase detector as 220-280 nm; and if the peak appears when the retention time is +/-0.05 min of the retention time of the impurity D in the control solution, determining that the compound D is contained.
Further, when the retention time is ± 0.05 minutes of the retention time of the impurity J in the control solution, it is determined that the compound J is contained.
Further, the content of the compound D, J is calculated by an external standard method, and the content calculation formula of the compound D is as follows:
Figure BDA0002334016410000052
in the formula: cS-concentration of impurity D in control solution,. mu.g/ml;
PS-content of impurity control D,%;
Cx-the concentration of the test solution,. mu.g/ml;
Ax-peak response of impurity D in the test solution;
As-impurity D peak response in control solution.
Further, the content calculation formula of the compound J is as follows:
Figure BDA0002334016410000051
in the formula: cS-concentration of impurity J in control solution,. mu.g/ml;
PS-content of impurity control J,%;
Cx-the concentration of the test solution,. mu.g/ml;
Ax-peak response of impurity J in the test solution;
As-impurity J peak response in control solution.
Specifically, the sample solution used in HPLC is prepared by taking a proper amount of betamethasone dipropionate raw material drug or preparation, precisely weighing, adding a diluent (after 35ml of water and 56ml of acetonitrile are mixed uniformly and placed at room temperature, diluting to 100ml of water) to dissolve and dilute to prepare a solution containing about 2.4mg of betamethasone dipropionate in each 1ml, and shaking uniformly.
The reference solution used in HPLC is prepared by respectively taking appropriate amount of reference substance of impurity D and impurity J, precisely weighing, adding diluent (prepared by mixing 35ml water and 56ml acetonitrile, standing at room temperature, and diluting to 100ml with water) to dissolve and dilute to obtain solution containing about 4.8 μ g of impurity D and 2.4 μ g of impurity J per 1ml, and shaking.
Specifically, the quantitative limit and the detection limit of the selected chromatographic system on the impurities D and/or J are researched and verified by S/N (signal to noise ratio).
Figure BDA0002334016410000061
Figure BDA0002334016410000062
The invention has the beneficial effects that:
1) the method for separating and identifying the impurities D and/or J can well separate the impurities D and J of the betamethasone dipropionate finished product from other impurities and main components possibly existing in the finished product within 23 minutes;
2) the method has high separation degree and high sensitivity; the specificity is strong; the reproducibility is good; the operation is simple and feasible.
Drawings
FIG. 1 HPLC chart of example 1.
FIG. 2 HPLC chart of example 3.
Figure 3 example 3 normal chromatographic conditions mixed solution HPLC profile.
FIG. 4 HPLC chromatogram of mixed solution at 28 ℃ of column temperature in example 4.
FIG. 5 HPLC chromatogram of mixed solution at 32 ℃ in example 4.
FIG. 6 example 4 HPLC chromatogram of a 0.9ml/min flow rate mixed solution.
FIG. 7 example 4 HPLC chromatogram of a mixed solution with a flow rate of 1.1 ml/min.
FIG. 8 example 4 HPLC chromatogram of a 34% mixed solution starting with mobile phase B.
FIG. 9 example 4 HPLC chromatogram of a 36% mixed solution of mobile phase B starting ratio.
FIG. 10 HPLC chromatogram of comparative example 1.
Detailed Description
The examples are given for the purpose of better illustration of the invention, but the invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention based on the above disclosure and fall within the scope of the invention.
Example 1 chromatographic conditions
A chromatographic column: octadecyl bonded silica gel (Thermo ODS Hypersil 100X 4mm, 3 μm or equivalent performance column).
The flow rate was 1.0 ml/min.
Detection wavelength: 254 nm.
Column temperature: at 30 ℃.
Mobile phase A: water-tetrahydrofuran (volume ratio 920: 80).
Mobile phase B: acetonitrile-tetrahydrofuran (volume ratio 920: 80).
And (3) an elution mode: the elution was carried out with a linear gradient, the elution gradient being shown in Table 1.
TABLE 1
Time (minutes) Mobile phase A (%) Mobile phase B (%)
0 65 35
10 65 35
10.1 20 80
15 20 80
15.1 65 35
23 65 35
Example 2 isolation and identification of impurities D and/or J
Test solution: taking a proper amount of raw material medicine or preparation of betamethasone dipropionate, precisely weighing, adding a diluent (after 35ml of water and 56ml of acetonitrile are mixed uniformly and placed at room temperature, diluting to 100ml of water) to dissolve and dilute to prepare a solution containing about 2.4mg of betamethasone dipropionate in each 1ml, and taking the solution as a test solution.
Control solution: respectively taking appropriate amount of impurity D and impurity J as reference substances, precisely weighing, adding diluent to dissolve and dilute to obtain solution containing about 4.8 μ g of impurity D and 2.4 μ g of impurity J per 1ml, and shaking to obtain reference substance solution.
Impurity D localization solution: taking a proper amount of the reference substance of the impurity D, precisely weighing, adding a diluent to dissolve and dilute the reference substance to prepare a solution containing about 5 mu g of the impurity D in each 1ml of the reference substance, and using the solution as the positioning solution of the impurity D.
Impurity J localization solution: taking a proper amount of the impurity J reference substance, precisely weighing, adding a diluent to dissolve and dilute to prepare a solution containing about 5 mu g of the impurity J in each 1ml, and taking the solution as an impurity J positioning solution.
10. mu.l each of the diluent, the impurity D and impurity J localization solution, the control solution, the sample solution and the mixed solution was sampled according to the method, and the sample was detected under the chromatographic conditions of example 1, and a chromatogram (FIG. 1) was recorded, and the integration results and the assay results are shown in Table 2 and Table 3, respectively.
TABLE 2
Figure BDA0002334016410000081
TABLE 3
Figure BDA0002334016410000082
And (4) conclusion: the blank solution (diluent) does not interfere with the detection of impurity D and impurity J; the main component of the sample and other known impurities possibly existing in the sample do not interfere the detection of the impurity D and the impurity J; the separation degree between the impurity D and the impurity J is 1.97, and the specificity of the method meets the requirement.
Example 3 detection Limit detection
The detection limit solution is continuously injected for 3 times, and the ratio (signal-to-noise ratio) of the main peak height to the noise is calculated. The detection was performed under the chromatography conditions of example 1, and a chromatogram (fig. 2) was recorded, with the integration results shown in table 4 and the detection limit measurement results shown in table 5.
TABLE 4
Figure BDA0002334016410000091
TABLE 5
Figure BDA0002334016410000092
And (4) conclusion: the detection limit concentration of the impurity D is 0.073 mug/ml, the concentration of the impurity D existing in the sample is 0.0030%, and the mean value of the signal-to-noise ratio is 16.6; the limit concentration of impurity J is 0.037 mug/ml, the concentration existing in the sample is 0.0016%, the mean value of the signal to noise ratio is 8.0, and the requirement of the limit test is met.
Example 3 chromatographic Condition durability test
Taking impurity test sample mixed solution, respectively using normal mobile phase, preset different mobile phase proportion, column temperature, column flow rate and chromatographic columns of the same model and different batches for testing, respectively testing after an instrument system is stabilized, recording the separation degree between peaks, recording a chromatogram (figures 3-9), wherein the integral result is shown in tables 6-12, and the durability test determination result of chromatographic condition change is shown in table 13.
TABLE 6 integration results of mixed solution chromatograms under normal chromatographic conditions
Figure BDA0002334016410000093
Figure BDA0002334016410000101
TABLE 7 column temperature 28 ℃ chromatogram integration results of mixed solution
Figure BDA0002334016410000102
TABLE 8 column temperature 32 ℃ chromatogram integration results of mixed solution
Figure BDA0002334016410000103
TABLE 9 chromatogram integration results of 0.9ml/min flow rate mixed solution
Figure BDA0002334016410000104
Figure BDA0002334016410000111
TABLE 10 chromatogram integration results of mixed solution at a flow rate of 1.1ml/min
Figure BDA0002334016410000112
TABLE 11 chromatogram integration results of a mixed solution of mobile phase B at an initial ratio of 34%
Figure BDA0002334016410000113
TABLE 12 chromatogram integration results of mixed solution with mobile phase B at initial ratio of 36%
Figure BDA0002334016410000114
Table 13 summary of the separation of impurities D and J from neighboring impurities for different chromatographic conditions
Figure BDA0002334016410000121
And (4) conclusion: when the chromatographic condition has small fluctuation (flow rate +/-0.1 ml/min, column temperature +/-2 deg.c and organic phase +/-1%), the separation degree between impurity D and impurity J and between two impurities and adjacent impurities is greater than 1.5, and the method has high durability.
Comparative example 1 separation of impurities D and/or J by EP10.0 pharmacopoeia method
At present, methods of EP10.0, USP42S1 and JP17 pharmacopeia are available for betamethasone dipropionate, wherein the related substance analysis method of the product of EP10.0 is the best for separating various known impurities. The compounds of impurity D and/or impurity J that may be present in the final product are highly similar in structure, whereas the EP10.0 related substance process is not effective in separating impurity D and/or impurity J that may be present in the final product (fig. 10), and the integration results are shown in table 14.
TABLE 14
Figure BDA0002334016410000122
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.

Claims (9)

1. A method for separating a compound D and/or a compound J is characterized in that an HPLC method is adopted for separation, the compound D, J is an impurity D, J in a betamethasone dipropionate product, a chromatographic column adopted in the HPLC separation process uses octadecyl bonded silica gel as a filler, a tetrahydrofuran aqueous solution as a mobile phase A and an acetonitrile-tetrahydrofuran solution as a mobile phase B for elution, and the compound D, J has a structural formula shown as a formula I and a formula II:
Figure FDA0002334016400000011
2. the method according to claim 1, wherein the degree of separation of the separated impurity D is 1.82 to 2.02.
3. The method according to claim 1, wherein the degree of separation of impurity J is 1.74 to 1.87.
4. The method according to claim 1, wherein the concentration of the tetrahydrofuran aqueous solution is 8% and the concentration of the tetrahydrofuran acetonitrile solution is 8%.
5. The method according to claim 1, characterized in that the gradient elution is carried out with mobile phase a and mobile phase B in the ratio:
0min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
10min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
10.1min, wherein the volume ratio of the mobile phase A to the mobile phase B is 20: 80;
15min, wherein the volume ratio of the mobile phase A to the mobile phase B is 20: 80;
15.1min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35;
and 23min, wherein the volume ratio of the mobile phase A to the mobile phase B is 65: 35.
6. A method for identifying a compound D and/or J, characterized in that the compound D and/or J is separated by the method of claim 1, while the wavelength of a high performance liquid phase detector is 220-280 nm; and if the peak appears when the retention time is +/-0.05 min of the retention time of the impurity D in the reference solution, determining that the compound D is contained.
7. The method according to claim 6, wherein the compound J is determined to be contained if a peak is generated when the retention time is ± 0.05 minutes of the retention time of the impurity J in the control solution.
8. The method of claim 6, wherein the amount of compound D, J is calculated by using an external standard method, and the amount of compound D is calculated according to the formula:
Figure FDA0002334016400000021
in the formula: cS-concentration of impurity D in control solution,. mu.g/ml;
PS-content of impurity control D,%;
Cx-the concentration of the test solution,. mu.g/ml;
Ax-peak response of impurity D in the test solution;
As-impurity D peak response in control solution.
9. The method according to claim 8, wherein the amount of compound J is calculated by the formula:
Figure FDA0002334016400000022
in the formula: cS-concentration of impurity J in control solution,. mu.g/ml;
PS-content of impurity control J,%;
Cx-the concentration of the test solution,. mu.g/ml;
Ax-peak response of impurity J in the test solution;
As-impurity J peak response in control solution.
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