CN115097046B - Method for separating rapamycin and impurities thereof - Google Patents
Method for separating rapamycin and impurities thereof Download PDFInfo
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- G—PHYSICS
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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- G—PHYSICS
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- 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
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
- G01N2030/3007—Control of physical parameters of the fluid carrier of temperature same temperature for whole column
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
- G01N2030/324—Control of physical parameters of the fluid carrier of pressure or speed speed, flow rate
Abstract
The invention discloses a method for separating rapamycin and impurities thereof, which comprises the steps of detecting a solution to be detected by adopting reverse-phase high performance liquid chromatography, wherein the conditions of the high performance liquid chromatography are as follows: mobile phase: the volume ratio of methanol, acetonitrile and water in the mobile phase A is 0-5:15-20:75-80; the volume ratio of methanol to acetonitrile in the mobile phase B is 40-50:50-60; elution mode: gradient elution. The method can effectively separate rapamycin and main process impurities thereof, and better control the quality of rapamycin, thereby improving the quality of the final product and ensuring the safety and effectiveness of clinical medication. Meanwhile, the separation method is simple and convenient to operate, low in cost and short in analysis time, and a simple, stable and reliable analysis and detection method is provided for research, development and production of products.
Description
Technical Field
The invention relates to the technical field of medicine analysis, in particular to a method for separating rapamycin and impurities thereof.
Background
Sirolimus (also known as "rapamycin") is a secondary metabolite secreted by streptomyces griseus in 1975, which was first discovered by scientists from the soil of the island of easter, and whose chemical structure belongs to the class of "trienolides". The novel immunosuppressant is initially used as a low-toxicity antifungal drug, has an immunosuppression effect in 1977, is used as a new drug for treating rejection of organ transplantation in the beginning of trial in 1989, and has good curative effect, low toxicity and no nephrotoxicity as shown by animal experiments and clinical application effects.
However, rapamycin is complex in chemical structure and may produce multiple homologs and isomers during fermentation, and the major process impurities include 12-desmethylrapamycin, 29-O-desmethylrapamycin and rapamycin hepta-isomers, 28-epi rapamycin. Therefore, the separation of rapamycin from its process impurities is of great significance.
Rapamycin related quality standards are not received in pharmacopoeias of various countries. The HPLC method adopted by the prior literature report data is as follows:
chromatographic condition 1: octadecylsilane chemically bonded silica (Kromasil C18X 4.6mm 5 μm) was used as filler, methanol-acetonitrile-water (70:15:30) was used as mobile phase, the flow rate was 1.0ml/min, the column temperature was 40℃and the detection wavelength was 277nm.
Chromatographic condition 2: octadecylsilane chemically bonded silica (Kromasil C18X 4.6mm 5 μm) was used as a filler, an ammonium formate solution (pH was adjusted to 3.8 with formic acid) of 20mmol/L was used as a mobile phase A, acetonitrile (containing 1% methyl tert-butyl ether) was used as a mobile phase B, and gradient elution was carried out in accordance with the following table at a flow rate of 1.5ml/min, a column temperature of 35℃and a sample pan temperature of 4℃were used, a detection wavelength of 277nm, and a sample amount of 20. Mu.l. The gradient elution procedure is as follows:
the detection of the above impurities by the HPLC method reported in the literature has defects and shortcomings: the desmethyl rapamycin impurity cannot be separated and completely coincides with rapamycin; the heptacyclic isomer of rapamycin coincides with rapamycin and cannot be isolated.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to provide a method for separating rapamycin and impurities thereof, which can accurately separate rapamycin and main process impurities thereof.
In order to achieve the above object, the present invention provides a method for separating rapamycin and impurities thereof, which comprises detecting a solution to be detected by reversed-phase high performance liquid chromatography under the following conditions:
mobile phase: the volume ratio of methanol, acetonitrile and water in the mobile phase A is 0-5:15-20:75-80; the volume ratio of methanol to acetonitrile in the mobile phase B is 40-50:50-60;
elution mode: gradient elution;
the gradient elution procedure described above was:
0-33min: mobile phase a volume changed from 40% to 30% and mobile phase B volume changed from 60% to 70%;
33-40min: 30% by volume of mobile phase A and 70% by volume of mobile phase B;
40-50min: mobile phase a volume changed from 30% to 20% and mobile phase B volume changed from 70% to 80%;
50.1-60min: the volume of mobile phase A was 40% and the volume of mobile phase B was 60%.
Further, the chromatographic column in the high performance liquid chromatography is medium-spectrum red RD-C18.
Further, the specification of the C18 reverse phase chromatography column was 4.6X105 mm, 3.0. Mu.m.
Further, the flow rate of the mobile phase in the high performance liquid chromatography is 0.8-1.2mL/min.
Further, the column temperature of the high performance liquid chromatography is: 45-55 ℃.
Further, the sample injection volume of the high performance liquid chromatography is as follows: 10-25 mu L.
Further, the rapamycin concentration in the test sample is: 0.4-1.0mg/mL.
Further, the detection wavelength of the high performance liquid chromatography is: 275-280nm.
Further, the impurity is selected from at least one of 12-desmethylrapamycin, 29-O-desmethylrapamycin and rapamycin heptaring isomers, 28-epi rapamycin.
Further, the flow rate of the mobile phase in the high performance liquid chromatography is 1.0mL/min; the column temperature of the high performance liquid chromatography is as follows: 50 ℃; the detection wavelength of the high performance liquid chromatography is as follows: 278nm.
The invention has the following beneficial effects:
the method for separating rapamycin and the impurities thereof provided by the invention can effectively separate rapamycin and main process impurities thereof (12-desmethylrapamycin, 29-O-desmethylrapamycin, rapamycin heptaring isomers and 28-epi rapamycin), the separation degree of the rapamycin and the impurities and the separation degree among the impurities are all more than 1.2, and the quality control of rapamycin can be better realized, so that the quality of a final product is improved, and the safety and effectiveness of clinical medication of the rapamycin are ensured. Meanwhile, the separation method is simple and convenient to operate, low in cost and short in analysis time, and a simple, stable and reliable analysis and detection method is provided for research, development and production of products.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a liquid chromatogram of example 1;
FIG. 2 is a liquid chromatogram of comparative example 1;
fig. 3 is a liquid chromatogram in comparative example 2.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Rapamycin is a macrolide immunosuppressant produced by fermentation, the chemical structure of rapamycin is complex, a plurality of homologs and isomers can be produced in the fermentation process, and mainly the technical impurities of 12-desmethyl rapamycin, 29-O-desmethyl rapamycin, rapamycin heptaring isomers and 28-epi rapamycin are represented by the following structural formulas:
in view of the reported literature that the above impurities cannot be effectively separated from rapamycin, the inventors of the present invention can effectively separate rapamycin from its process impurities by changing the mobile phase and elution procedure of high performance liquid chromatography, particularly by changing the addition ratio of methanol and the retention time of the compound.
Based on this, the invention provides a method for separating rapamycin and impurities thereof, which utilizes reverse phase high performance liquid chromatography to detect a solution to be detected containing rapamycin and main process impurities thereof, and comprises the following steps:
(1) Preparing a mobile phase: the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A contains methanol, acetonitrile and water in a volume ratio of 0-5:15-20:75-80; the volume ratio of methanol to acetonitrile contained in the mobile phase B is 40-50:50-60.
The inventor can initially analyze that different hydroxyl groups at different positions can have different retention times in a methanol mobile phase according to the characteristics of structural formulas of rapamycin and impurities thereof, so that a certain amount of methanol is added in the mobile phase, and compounds can be effectively separated.
(2) Preparation of the solution to be tested
Preparing acetonitrile solution for a sample to be tested into the following concentration: 0.4-1.0mg/mL of the solution to be tested.
The rapamycin concentration adopted in the sample to be detected can ensure effective separation of various substances.
(3) And (3) sample loading detection: and (3) injecting the solution to be detected into a liquid chromatograph, and detecting the solution to be detected containing rapamycin and main process impurities thereof. Specifically, conditions for high performance liquid chromatography detection are as follows:
chromatographic column: octadecylsilane chemically bonded silica was used as a filler material, and the specification was 4.6X105 mm, 3.0. Mu.m.
In some embodiments, the chromatographic column is medium-spectrum red RD-C18.
The inventor finds that the chromatographic column has high carbon content, small surface polarity and high separation degree by adopting the special chromatographic column to analyze the spectral red, and has better separation capability for rapamycin and impurities thereof.
Depending on the change in mobile phase, the invention correspondingly selects the appropriate elution regime and changes the elution procedure to change the retention time of the compound.
In some embodiments, the elution mode: gradient elution.
In some embodiments, the gradient elution procedure is:
0-33min: mobile phase a volume changed from 40% to 30% and mobile phase B volume changed from 60% to 70%;
33-40min: 30% by volume of mobile phase A and 70% by volume of mobile phase B;
40-50min: mobile phase a volume changed from 30% to 20% and mobile phase B volume changed from 70% to 80%;
50.1-60min: the volume of mobile phase A was 40% and the volume of mobile phase B was 60%.
By adopting the mode for elution, the rapamycin and impurities thereof are separated, and the detection accuracy is ensured.
In some embodiments, the mobile phase flow rate in high performance liquid chromatography is 0.8-1.2mL/min. Preferably, the flow rate of the mobile phase in high performance liquid chromatography is 1mL/min.
In some embodiments, the column temperature of the high performance liquid chromatography is: 45-55 ℃. Preferably, the column temperature in high performance liquid chromatography is: 50 ℃.
In high performance liquid chromatography detection, the column temperature not only affects the life of the chromatographic column fixing liquid, but also affects the separation efficiency and analysis time, the retention time of the compound and the peak shape of the chromatographic peak. The adoption of the column temperature is beneficial to the separation of rapamycin and impurities thereof.
In some embodiments, the sample volume of the hplc at the time of detection is: 10-25 mu L. Preferably, the sample injection volume of the high performance liquid chromatography is: 10 mu L.
In some embodiments, the detection wavelength of the high performance liquid chromatography is: 275-280nm. Preferably, the detection wavelength of the high performance liquid chromatography is: 278nm.
The separation degree of rapamycin and impurities thereof detected by high performance liquid chromatography is more than or equal to 1.50, and the method has better separation degree, and further illustrates that the detection method provided by the invention can realize the separation of rapamycin and impurities thereof.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The present embodiment provides a method for separating rapamycin and impurities thereof, comprising the steps of:
(1) Preparing a mobile phase: the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A comprises acetonitrile and water in a volume ratio of 20:80; the volume ratio of methanol and acetonitrile contained in the mobile phase B is 40:60.
(2) Preparation of the solution to be tested
Wherein, rapamycin concentration in the sample to be measured is: 1.0mg/mL.
(3) And (3) sample loading detection: and (3) injecting the solution to be detected into a liquid chromatograph, and detecting the solution to be detected containing rapamycin and main process impurities thereof.
The conditions for high performance liquid chromatography detection are as follows:
chromatographic column: mid-spectrum red RD-C18, specification 4.6X250 mm,3.0 μm.
Elution mode: gradient elution; the gradient elution procedure was:
0-33min: mobile phase a volume changed from 40% to 30% and mobile phase B volume changed from 60% to 70%;
33-40min: 30% by volume of mobile phase A and 70% by volume of mobile phase B;
40-50min: mobile phase a volume changed from 30% to 20% and mobile phase B volume changed from 70% to 80%;
50.1-60min: the volume of mobile phase A was 40% and the volume of mobile phase B was 60%.
The flow rate of the mobile phase in the high performance liquid chromatography is 1.0mL/min; the column temperature was: 50 ℃; the sample injection volume is as follows: 10. Mu.L; the detection wavelength is as follows: 278nm.
A liquid chromatogram, as shown in fig. 1; the separation of rapamycin and its impurities is shown in table 1:
table 1 analysis results
As can be seen from Table 1 and FIG. 1, rapamycin and impurities thereof in the solution to be detected can be effectively separated, the separation degree is more than 1.20, the peak shape is good, the theoretical plate number is more than 10000, and the tailing factor is 0.95-1.15, thereby conforming to the standard.
Comparative example 1
The comparative example differs from example 1 in that the conditions for high performance liquid chromatography detection employed in the comparative example are as follows:
octadecylsilane chemically bonded silica (Kromasil C18X 4.6mm 5 μm) was used as a filler, an ammonium formate solution (pH was adjusted to 3.8 with formic acid) of 20mmol/L was used as a mobile phase A, acetonitrile (containing 1% methyl tert-butyl ether) was used as a mobile phase B, and gradient elution was carried out in accordance with the following table at a flow rate of 1.5ml/min, a column temperature of 35℃and a sample pan temperature of 4℃were used, a detection wavelength of 277nm, and a sample amount of 20. Mu.l. The gradient elution procedure is as follows:
the liquid chromatogram is shown in FIG. 2, and the analysis results of the separation of rapamycin and its impurities are shown in Table 2 and below:
table 2 analysis results
From the results shown in FIG. 2 and Table 2, the two impurities (12-desmethylrapamycin and 29-O-desmethylrapamycin) before the main peak of rapamycin could not be effectively separated, and the number of theoretical detected impurities was 8, and the number of actually detected impurities was 4.
Comparative example 2
The comparative example differs from example 1 in that the conditions for high performance liquid chromatography detection employed in the comparative example are as follows:
octadecylsilane chemically bonded silica (Kromasil C18X 4.6mm 5 μm) was used as filler, methanol-acetonitrile-water (70:15:30) was used as mobile phase, the flow rate was 1.0ml/min, the column temperature was 40℃and the detection wavelength was 277nm.
The liquid chromatogram is shown in FIG. 3, and the analysis results of the separation of rapamycin and its impurities are shown in Table 3 and below:
TABLE 3 analysis results
From the results of this comparative example, it was not possible to separate rapamycin from the other 4 impurities by isocratic elution, wherein 12-desmethylrapamycin and 29-O-desmethylrapamycin completely overlapped, 28-epi rapamycin and rapamycin heptacyclic isomer completely overlapped, the number of theoretical detected impurities was 8, and the number of actually detected impurities was 4.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (7)
1. The method for separating rapamycin and impurities thereof is characterized by comprising the steps of detecting a solution to be detected by adopting reverse-phase high performance liquid chromatography, wherein the conditions of the high performance liquid chromatography are as follows:
mobile phase: the volume ratio of methanol, acetonitrile and water in the mobile phase A is 0-5:15-20:75-80; the volume ratio of methanol to acetonitrile in the mobile phase B is 40-50:50-60;
elution mode: gradient elution;
the gradient elution procedure was:
0-33min: mobile phase a volume changed from 40% to 30% and mobile phase B volume changed from 60% to 70%;
33-40min: 30% by volume of mobile phase A and 70% by volume of mobile phase B;
40-50min: mobile phase a volume changed from 30% to 20% and mobile phase B volume changed from 70% to 80%;
50.1-60min: mobile phase a was 40% by volume and mobile phase B was 60% by volume;
the chromatographic column in the high performance liquid chromatography is medium-spectrum red RD-C18;
the specification of the C18 reversed phase chromatographic column is 4.6X250 mm,3.0 μm;
the impurities are 12-desmethylrapamycin, 29-O-desmethylrapamycin, rapamycin heptaring isomers and 28-epi rapamycin.
2. The method of claim 1, wherein the mobile phase in the high performance liquid chromatography has a flow rate of 0.8-1.2mL/min.
3. The method of claim 2, wherein the column temperature of the high performance liquid chromatography is: 45-55 ℃.
4. The method of claim 3, wherein the sample volume of the high performance liquid chromatograph is: 10-25 mu L.
5. The method of claim 4, wherein the rapamycin concentration in the test solution is: 0.4-1.0mg/mL.
6. The method of claim 5, wherein the detection wavelength of the high performance liquid chromatography is: 275-280nm.
7. The method of claim 6, wherein the mobile phase in the high performance liquid chromatography has a flow rate of 1.0mL/min; the chromatographic column temperature of the high performance liquid chromatography is as follows: 50 ℃; the detection wavelength of the high performance liquid chromatography is as follows: 278nm.
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Citations (4)
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|---|---|---|---|---|
| WO2001014387A1 (en) * | 1999-08-24 | 2001-03-01 | Ariad Gene Therapeutics, Inc. | 28-epirapalogs |
| CN101522691A (en) * | 2006-11-27 | 2009-09-02 | 泰尔茂株式会社 | Process for producing o-alkylated rapamycin derivative, and o-alkylated rapamycin derivative |
| CN105301159A (en) * | 2015-10-29 | 2016-02-03 | 无锡福祈制药有限公司 | High performance liquid chromatography analysis method of sirolimus |
| CN110146621A (en) * | 2019-06-13 | 2019-08-20 | 国药集团致君（深圳）制药有限公司 | The content assaying method of polymer in cephalosporin analog antibiotic drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3813946A4 (en) * | 2018-06-15 | 2022-06-01 | Anakuria Therapeutics, Inc. | Rapamycin analogs and uses thereof |
| EP4069223A4 (en) * | 2019-12-05 | 2023-12-20 | Janssen Pharmaceutica NV | Rapamycin analogs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001014387A1 (en) * | 1999-08-24 | 2001-03-01 | Ariad Gene Therapeutics, Inc. | 28-epirapalogs |
| CN101522691A (en) * | 2006-11-27 | 2009-09-02 | 泰尔茂株式会社 | Process for producing o-alkylated rapamycin derivative, and o-alkylated rapamycin derivative |
| CN105301159A (en) * | 2015-10-29 | 2016-02-03 | 无锡福祈制药有限公司 | High performance liquid chromatography analysis method of sirolimus |
| CN110146621A (en) * | 2019-06-13 | 2019-08-20 | 国药集团致君（深圳）制药有限公司 | The content assaying method of polymer in cephalosporin analog antibiotic drug |
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