CN110780005A - Analysis method of Cribolol raw material and synthetic intermediate thereof - Google Patents
Analysis method of Cribolol raw material and synthetic intermediate thereof Download PDFInfo
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Abstract
The invention discloses a method for analyzing a Clibolol raw material and a synthetic intermediate thereof, which is characterized in that a test solution is a mixed solution of Clibolol (API), starting materials (SM1, SM2) and intermediates (M1, M2, M3, M4); wherein the concentration of the Cliboron (API) is 0.5-1.5mg/mL, the concentration of each starting material (SM1, SM2) is 0.5-0.15mg/mL, and the concentration of each intermediate (M1, M2, M3, M4) is 0.05-0.15 mg/mL; detecting the test solution by using a high performance liquid chromatograph; the mobile phase is a mixed solution of a mobile phase A added with a certain amount of acidic reagent in water and a mobile phase B added with a certain amount of acetonitrile of the acidic reagent, and the flow rate of the mobile phase is 0.8-1.2 mL/min. The method realizes simple, rapid and accurate separation and detection of the Kriboren and the synthetic intermediate thereof, and solves the separation and detection problem of the Kriboren and the synthetic intermediate thereof.
Description
Technical Field
The invention relates to the field of analysis of medicine raw materials, in particular to a method for analyzing a kreb raw material and a synthetic intermediate thereof.
Background
Crisabiole (Crisabiole) is a phosphodiesterase 4(PDE4) inhibitor which results in increased intracellular cyclic adenosine monophosphate (cAMP) levels for the treatment of fungal infections, more particularly onychomycosis and/or dermatophytic infections. The drug was approved by the U.S. Food and Drug Administration (FDA) for marketing at 2016, 12 months, was developed by the Anacor pharmaceutical company and is responsible for marketing in the united states under the trade name crisabaroll. The chemical name is 5- (4-cyanophenoxy) -1, 3-dihydro-1-hydroxy-2, 1-benzoxaborole, the English name is 4- ((1-hydroxy-1,3-dihydrobenzo [ c ] [1,2] oxozol-5-yl) oxy) benzonitril, and the chemical structural formula is shown as the formula (I): the structural formula is as follows:
currently, the quality standards of Cribacrole (Crisabiole) are not yet included in the latest edition of the United states Pharmacopeia (United states Pharmacopeia) since it is soon marketed. In the published documents or patents, there is no method for analyzing and detecting the content of Crisabiole (Crisabiole) or impurities. Therefore, the product has no analysis standard which can be referred to at the present stage, and the application and popularization of the product are hindered.
Therefore, it is necessary to establish a stable and efficient analysis method for cristoborol (crisabarol) and its synthesis intermediates.
The following starting materials and intermediates were used for this analytical method:
disclosure of Invention
In order to overcome the defects in the prior art, the embodiment of the invention provides an analysis method for a kreb raw material and a synthetic intermediate thereof, which realizes simple, rapid and accurate separation and detection of the kreb and the synthetic intermediate thereof, solves the separation and detection problem of the kreb and the synthetic intermediate thereof, and ensures the quality controllability of the kreb raw material.
In order to achieve the above object, the embodiments of the present application disclose a method for analyzing a kreb raw material and a synthetic intermediate thereof, wherein a sample solution is a mixed solution of kreb (API), starting materials (SM1, SM2), and intermediates (M1, M2, M3, M4); wherein the concentration of the Cliboron (API) is 0.5-1.5mg/mL, the concentration of each starting material (SM1, SM2) is 0.5-0.15mg/mL, and the concentration of each intermediate (M1, M2, M3, M4) is 0.05-0.15 mg/mL;
detecting the test solution by using a high performance liquid chromatograph; the mobile phase is a mixed solution of a mobile phase A added with a certain amount of acidic reagent in water and a mobile phase B added with a certain amount of acetonitrile of the acidic reagent, and the flow rate of the mobile phase is 0.8-1.2 mL/min.
Preferably, the acidic reagent is trifluoroacetic acid or phosphoric acid or glacial acetic acid, and the concentration of the acidic reagent is 0.02-0.1%.
Preferably, the type of the chromatographic column is Excel3C18-PFP, and the length of the chromatographic column is 250mm, and the diameter of the chromatographic column is 4.6 mm.
Preferably, the volume ratio of the mobile phase A to the mobile phase B is (95-100): 0-5) (v: v).
Preferably, the volume ratio of the water to the acidic reagent in the mobile phase a is 1000: (0.02-1.0) (v: v).
Preferably, the volume ratio of the acetonitrile to the acidic reagent in the mobile phase B is 1000: (0.02-1.0) (v: v).
Preferably, the sample volume of the test solution is 8-20 μ L, and the column temperature of the chromatographic column is 30-40 ℃.
Preferably, the detection wavelength is 230-250 nm.
Preferably, the filler of the chromatographic column is pentafluorophenyl octadecylsilane bonded silica gel.
The invention has the following beneficial effects:
1. the method uses a high performance liquid chromatograph, does not need other instruments, adopts a conventional pentafluorophenyl octadecylsilane bonded silica gel column as a chromatographic column, is a chromatographic column commonly used in laboratories, and has a short supply period for manufacturers. The used reagent and test solution are common reagents in a laboratory, so that the detection cost can be effectively reduced, and the detection efficiency is improved;
2. the invention can effectively separate the Cliborol and each synthesis intermediate thereof; the process of the synthesis reaction can be accurately monitored; can carry out effective impurity detection on each synthetic intermediate;
3. the invention improves the response and symmetry of chromatographic peaks by optimizing parameters such as mobile phase components, mobile phase flow rate, chromatographic column temperature, sample injection volume and the like. The separation and detection problems of the Cliboroluo and the synthetic intermediate thereof are solved, so that the quality controllability of the Cliboroluo raw material or the preparation is ensured.
In order to make the aforementioned and other objects, features and advantages of the invention comprehensible, preferred embodiments accompanied with figures are described in detail below.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is an HPLC chromatogram of Cliborol and its synthetic intermediates, starting materials under the conditions of example 1;
FIG. 2 is an HPLC chromatogram of Cliborol and its synthetic intermediates, starting materials under the conditions of example 2;
FIG. 3 is an HPLC chromatogram of Cliborol and its synthetic intermediates, starting materials under the conditions of example 3;
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The high performance liquid chromatograph used in the invention is Agilent 1260 II, and the chromatographic column is Excel3C 18-PFP; the reagent used in the invention comprises trifluoroacetic acid, phosphoric acid, glacial acetic acid, acetonitrile and water.
The method uses a high performance liquid chromatograph, does not need other instruments, adopts a conventional pentafluorophenyl octadecylsilane bonded silica gel column as a chromatographic column, is a chromatographic column commonly used in laboratories, and has a short supply period for manufacturers. The used reagent and test solution are common reagents in laboratories, so that the detection cost can be effectively reduced, and the detection efficiency is improved.
Example 1
1. Instruments and conditions:
high performance liquid chromatograph: agilent 1260 II
A chromatographic column: excel3C18-PFP 250 x 4.6mm
Mobile phase A: 0.05% aqueous trifluoroacetic acid (v: v)
Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v: v)
Flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 250nm
Sample introduction volume: 10uL
2. The implementation steps are as follows:
weighing 100mg of krebs, 10mg of each intermediate and each starting material respectively, placing the krebs, the intermediates and the starting materials in a 100mL measuring flask, dissolving and fixing the volume to obtain a sample solution.
10uL of the above solution was injected into a high performance liquid chromatograph, and a chromatogram was recorded, and the results are shown in FIG. 1.
As can be seen from fig. 1: retention time of SM1 was 22.347min, retention time of SM2 was 20.810min, retention time of M1 was 34.458min, retention time of M2 was 31.180min, retention time of M3 was 35.159min, retention time of M4 was 36.610min, and retention time of API was 27.285 min.
The invention improves the response and symmetry of chromatographic peaks by optimizing parameters such as mobile phase components, mobile phase flow rate, chromatographic column temperature, sample injection volume and the like. The separation and detection problems of the Cliboroluo and the synthetic intermediate thereof are solved, so that the quality controllability of the Cliboroluo raw material or the preparation is ensured.
The invention can effectively separate the Cliborol and each synthesis intermediate thereof; the process of the synthesis reaction can be accurately monitored; can effectively detect impurities of each synthetic intermediate.
Example 2
1. Instruments and conditions:
high performance liquid chromatograph: agilent 1260 II
A chromatographic column: excel3C18-PFP 250 x 4.6mm
Mobile phase A: 0.05% aqueous trifluoroacetic acid (v: v)
Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v: v)
Flow rate: 1.0mL/min
Column temperature: 30 deg.C
Detection wavelength: 250nm
Sample introduction volume: 10uL
2. The implementation steps are as follows:
weighing 100mg of krebs, 10mg of each intermediate and the initial material respectively, placing the krebs, the intermediate and the initial material into a 100mL measuring flask, dissolving and fixing the volume to obtain a sample solution. 10uL of the above solution was injected into a high performance liquid chromatograph, and a chromatogram was recorded, and the result is shown in FIG. 2.
As can be seen from fig. 2: retention time of SM1 was 22.316min, retention time of SM2 was 21.920min, retention time of M1 was 34.948min, retention time of M2 was 32.391min, retention time of M3 was 35.512min, retention time of M4 was 36.847min, and retention time of API was 28.481 min.
The invention improves the response and symmetry of chromatographic peaks by optimizing parameters such as mobile phase components, mobile phase flow rate, chromatographic column temperature, sample injection volume and the like. The separation and detection problems of the Cliboroluo and the synthetic intermediate thereof are solved, so that the quality controllability of the Cliboroluo raw material or the preparation is ensured.
The invention can effectively separate the Cliborol and each synthesis intermediate thereof; the process of the synthesis reaction can be accurately monitored; can effectively detect impurities of each synthetic intermediate.
Example 3
1. Instruments and conditions:
high performance liquid chromatograph: agilent 1260 II
A chromatographic column: excel3C18-PFP 250 x 4.6mm
Mobile phase A: 0.1% aqueous trifluoroacetic acid (v: v)
Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile (v: v)
Flow rate: 1.0mL/min
Column temperature: 40 deg.C
Detection wavelength: 250nm
Sample introduction volume: 10uL
2. The implementation steps are as follows:
weighing 100mg of krebs, 10mg of each intermediate and the initial material respectively, placing the krebs, the intermediate and the initial material into a 100mL measuring flask, dissolving and fixing the volume to obtain a sample solution. 10uL of the above solution was injected into a high performance liquid chromatograph, and a chromatogram was recorded, and the result is shown in FIG. 3.
As can be seen from fig. 3: retention time of SM1 was 22.290min, retention time of SM2 was 20.761min, retention time of M1 was 34.403min, retention time of M2 was 31.089min, retention time of M3 was 35.119min, retention time of M4 was 36.574min, and retention time of API was 27.196 min.
The invention improves the response and symmetry of chromatographic peaks by optimizing parameters such as mobile phase components, mobile phase flow rate, chromatographic column temperature, sample injection volume and the like. The separation and detection problems of the Cliboroluo and the synthetic intermediate thereof are solved, so that the quality controllability of the Cliboroluo raw material or the preparation is ensured.
The invention can effectively separate the Cliborol and each synthesis intermediate thereof; the process of the synthesis reaction can be accurately monitored; can effectively detect impurities of each synthetic intermediate.
The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.
Claims (9)
1. A method for analyzing a Cribolol raw material and a synthetic intermediate thereof is characterized in that,
the test solution is a mixed solution of Clibolol (API), starting materials (SM1, SM2) and intermediates (M1, M2, M3, M4); wherein the concentration of the Cliboron (API) is 0.5-1.5mg/mL, the concentration of each starting material (SM1, SM2) is 0.5-0.15mg/mL, and the concentration of each intermediate (M1, M2, M3, M4) is 0.05-0.15 mg/mL;
detecting the test solution by using a high performance liquid chromatograph; the mobile phase is a mixed solution of a mobile phase A added with a certain amount of acidic reagent in water and a mobile phase B added with a certain amount of acetonitrile of the acidic reagent, and the flow rate of the mobile phase is 0.8-1.2 mL/min.
2. The method for analyzing a kreb's raw material and its synthesis intermediate as claimed in claim 1, characterized in that the acidic reagent is trifluoroacetic acid or phosphoric acid or glacial acetic acid, and the concentration of the acidic reagent is 0.02-0.1%.
3. The method for analyzing Krebs raw material and synthetic intermediates thereof according to claim 1, wherein the type of the column is Excel3C18-PFP, the length of the column is 250mm, and the diameter of the column is 4.6 mm.
4. The method for analyzing Cliborol raw material and its synthesis intermediate as claimed in claim 1, wherein the volume ratio of the mobile phase A and the mobile phase B is (95-100): (0-5) (v: v).
5. The method for analyzing a kreb's raw material and a synthetic intermediate thereof as claimed in claim 1, wherein the volume ratio of water to the acidic reagent in the mobile phase a is 1000: (0.02-1.0) (v: v).
6. The method for analyzing a kreb's raw material and a synthetic intermediate thereof as claimed in claim 1, wherein the volume ratio of acetonitrile to the acidic reagent in the mobile phase B is 1000: (0.02-1.0) (v: v).
7. The method for analyzing a kreb's raw material and its synthetic intermediate as claimed in claim 1, wherein the sample volume of the sample solution is 8-20 μ L, and the column temperature of the chromatographic column is 30-40 ℃.
8. The method for analyzing Klibolol material and its synthesis intermediate as claimed in claim 1, wherein the detection wavelength is 230-250 nm.
9. The method of claim 1, wherein the packing material of the chromatography column is pentafluorophenyloctadecylsilane bonded silica.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114216987A (en) * | 2021-12-22 | 2022-03-22 | 湖南方盛制药股份有限公司 | Method for analyzing cefixime tablets by high performance liquid chromatography |
Citations (3)
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| WO2017193914A1 (en) * | 2016-05-09 | 2017-11-16 | 苏州科睿思制药有限公司 | Crystal forms of crisaborole in free form and preparation method and use thereof |
| CN108047261A (en) * | 2018-01-10 | 2018-05-18 | 苏州旺山旺水生物医药有限公司 | A kind of preparation method of gram of vertical boron sieve |
| CN110357792A (en) * | 2019-08-19 | 2019-10-22 | 武汉轻工大学 | A kind of preparation method of gram of vertical boron sieve intermediate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017193914A1 (en) * | 2016-05-09 | 2017-11-16 | 苏州科睿思制药有限公司 | Crystal forms of crisaborole in free form and preparation method and use thereof |
| CN108047261A (en) * | 2018-01-10 | 2018-05-18 | 苏州旺山旺水生物医药有限公司 | A kind of preparation method of gram of vertical boron sieve |
| CN110357792A (en) * | 2019-08-19 | 2019-10-22 | 武汉轻工大学 | A kind of preparation method of gram of vertical boron sieve intermediate |
Non-Patent Citations (1)
| Title |
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| ANNA DEMURTAS ET AL.: "Development and validation of a simple method for the extraction and quantification of crisaborole in skin layers", 《BIOMEDICAL CHROMATOGRAPHY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114216987A (en) * | 2021-12-22 | 2022-03-22 | 湖南方盛制药股份有限公司 | Method for analyzing cefixime tablets by high performance liquid chromatography |
| CN114216987B (en) * | 2021-12-22 | 2024-02-02 | 湖南方盛制药股份有限公司 | Method for analyzing cefixime tablets by high performance liquid chromatography |
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