CN115236236A - Linezolid and separation and analysis method of enantiomers in preparation thereof - Google Patents
Linezolid and separation and analysis method of enantiomers in preparation thereof Download PDFInfo
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- CN115236236A CN115236236A CN202210887443.1A CN202210887443A CN115236236A CN 115236236 A CN115236236 A CN 115236236A CN 202210887443 A CN202210887443 A CN 202210887443A CN 115236236 A CN115236236 A CN 115236236A
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- G—PHYSICS
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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
- 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
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G—PHYSICS
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Abstract
The invention discloses a separation and analysis method of linezolid and enantiomers in a preparation thereof, which is a Supercritical Fluid Chromatography (SFC) method, adopts a chiral chromatographic column, and takes carbon dioxide and a modifier as mobile phases. The separation and analysis method for the enantiomers of the linezolid and the preparation thereof has the advantages of short analysis time, good separation effect between the linezolid and the enantiomers thereof, higher sensitivity, avoidance of the use of a large amount of n-hexane by a mobile phase, greenness, environmental friendliness, capability of solving the problem that an injection sample is difficult to directly analyze chiral isomerism by adopting a normal phase chromatography system, and strong popularization. Has reference significance for preparing high-purity linezolid.
Description
Technical Field
The invention relates to the technical field of linezolid detection, and particularly relates to a separation and analysis method for linezolid and enantiomers in a preparation thereof.
Background
Linezolid, (S) -N- [ [3- (3-fluoro-4-morpholinylphenyl) -2-oxo-5-oxazolidinyl ] methyl ] acetamide, the first oxazolidinone antibiotic that was synthesized artificially, was approved by the FDA in the united states in 2000 for the treatment of infections caused by gram-positive cocci, and was approved for marketing in china in 2006. The formulations on the market at present in China comprise linezolid tablets, linezolid dry suspension and linezolid glucose injection.
Impurities are key quality attributes of a drug, and may affect the safety and effectiveness of the drug. The research on impurities is the main content of in vitro pharmaceutical research, and is throughout the whole life cycle of research, development, production, change after marketing, and the like of medicines. The daily dose of linezolid is 1.2g, and the requirement of the ICH impurity research guiding principle and the Chinese pharmacopoeia medicine impurity analysis guiding principle is reflected in the detection report for the impurity with the content of more than 0.05%. And in single enantiomer pharmaceuticals the other enantiomers and diastereomers, which may coexist, should be checked as impurities.
Methods for detecting the enantiomers of linezolid and its preparations include capillary electrophoresis and high performance liquid chromatography. The high performance liquid chromatography mainly adopts a chiral chromatographic column and measures under the condition of normal phase chromatography. Practice shows that the capillary electrophoresis method needs to add specific chiral cyclodextrin into a running medium, so that the cost is high, and the detection sensitivity of chiral isomers is low, which is about 1 percent. The chromatographic column type adopted by the chiral high performance liquid chromatography mainly relates to CHIRALPAKAD-H, AY-H, IA, DMB and the like. The main problems of the above method are: 1. is not suitable for direct sample injection analysis of linezolid glucose injection samples; 2. DMB filling has already stopped production; 3. the mobile phase needs a large amount of normal hexane, which is not beneficial to environmental protection and the safety of experimenters.
Based on the defects of the linezolid enantiomer determination method, a green and environment-friendly analysis method which has high sensitivity and is suitable for an aqueous matrix sample needs to be established, so that the method is suitable for the quality control of linezolid and a preparation thereof, in particular the quality control of linezolid glucose injection.
Disclosure of Invention
The invention aims to provide a separation and analysis method of linezolid and enantiomers in a preparation thereof, aiming at the defects in the prior art, the method is a Supercritical Fluid Chromatography (SFC) method, adopts a chiral chromatographic column, takes carbon dioxide and a modifier as a mobile phase, has high analysis speed, can realize good separation of linezolid and enantiomers through screening of the chromatographic column, simultaneously ensures higher detection sensitivity, is equivalent to 0.005 percent, and is a generalizable method for determining enantiomer impurities in linezolid.
In order to realize the purpose, the invention adopts the technical scheme that:
the invention provides a separation and analysis method of linezolid and enantiomers in a preparation thereof, wherein the detection method is a supercritical fluid chromatography method, and comprises the following steps:
step 1) dissolving a linezolid raw material by adopting methanol or acetonitrile to obtain a sample to be detected; ultrasonically treating the linezolid solid preparation by using methanol or acetonitrile, centrifuging and filtering to obtain a sample to be detected; after the solvent is volatilized by the linezolid liquid preparation, re-dissolving methanol or acetonitrile to obtain a sample to be detected;
step 2) detecting by using carbon dioxide and a modifier as a mobile phase, a chiral chromatographic column as a stationary phase and an ultraviolet detector;
wherein the modifier is one or more of methanol, ethanol and acetonitrile.
Further, the concentration of linezolid in a sample to be detected of the linezolid raw material or the linezolid solid preparation or the linezolid liquid preparation is 5-10 mg/mL -1 。
Further, the proportion of the modifier methanol in the mobile phase is 0-40% (v/v).
Further preferably, the proportion of the modifier methanol in the mobile phase is 20 to 30% (v/v).
Further, the proportion of the modifying agent ethanol in the mobile phase is 0-40% (v/v).
Further preferably, the proportion of the modifier ethanol in the mobile phase is 5-15% (v/v).
Further, the volume ratio of methanol to acetonitrile in the modifier methanol-acetonitrile mixed solvent is 100.
Further preferably, the volume ratio of methanol to acetonitrile in the modifier methanol-acetonitrile mixed solvent is 100.
Furthermore, the filler active group of the chromatographic column is cellulose or amylose type chiral stationary liquid, and the column temperature is 25-40 ℃.
Further preferably, the filler active group of the chromatographic column is amylose type chiral stationary liquid, and the column temperature is 30-40 ℃.
Furthermore, the sample injection volume of the chromatographic column is 1-10 mu L, and the flow rate is 1.0-2.5 mL/min -1 。
Further preferably, the sample injection volume of the chromatographic column is 2 μ L, and the flow rate is 1.5 mL/min -1 。
Other suitable columns may be selected and the flow rate may be adjusted to suit the selected column size. The sample injection volume can be adjusted to a sample injection volume adapted to the sample loading of the chromatographic column or the response of the detector.
Further, the limit of detection of linezolid is about 0.5. Mu.g.mL-1 (about 0.005%).
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
the separation and analysis method for the enantiomers of linezolid and the preparation thereof has the advantages of short analysis time, good separation effect between linezolid and the enantiomers thereof, high sensitivity, avoidance of application of a large amount of n-hexane in a mobile phase, greenness, environmental friendliness, capability of solving the problem that an injection sample is difficult to directly analyze chiral isomers by adopting a normal phase chromatographic system, and strong popularization. Has reference significance for preparing high-purity linezolid.
Drawings
FIG. 1 is a typical chromatogram of a mixed control solution of linezolid and its enantiomers in an embodiment of the present invention, wherein the chromatographic peak is 1-linezolid enantiomer (10 μ g. ML-1); 2-linezolid (10 mg. ML-1).
FIG. 2 is a typical chromatogram of linezolid (10 mg. ML-1).
FIG. 3 is a typical chromatogram of an enantiomer of linezolid (2. Mu.g. ML-1).
Figure 4 is a typical chromatogram of linezolid tablet (source a) in an example of the invention.
Figure 5 is a typical chromatogram of linezolid tablet (source B) in an example of the invention.
FIG. 6 is a typical chromatogram of a linezolid glucose injection (source A) in an example of the invention.
Fig. 7 is a typical chromatogram of linezolid glucose injection (source C) in an example of the invention.
Fig. 8 is a typical chromatogram of linezolid glucose injection (source D) in an example of the invention.
FIG. 9 is a typical chromatogram of a linezolid glucose injection (source E) in an example of the invention.
FIG. 10 is a typical chromatogram of a mixed control solution of linezolid and its enantiomers in another embodiment of the invention, wherein the chromatographic peak is 1-linezolid enantiomer (0.25 mg. Multidot.mL-1); 2-linezolid (0.25 mg. ML-1).
Detailed Description
The invention is further described with reference to the following drawings and specific examples, which are not intended to be limiting. It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
The invention provides a separation and analysis method of linezolid and enantiomers in a preparation thereof, wherein the detection method is a supercritical fluid chromatography method, and comprises the following steps:
step 1) dissolving a linezolid raw material by adopting methanol to obtain a sample to be detected; ultrasonically treating the linezolid solid preparation by using methanol or acetonitrile, centrifuging and filtering to obtain a sample to be detected; after volatilizing the solvent, re-dissolving the linezolid liquid preparation with methanol or acetonitrile to obtain a sample to be detected;
step 2) detecting by using carbon dioxide and a modifier as a mobile phase, a chiral chromatographic column as a stationary phase and an ultraviolet detector;
wherein the modifier is one or more of methanol, ethanol and acetonitrile.
Further, the concentration of the linezolid in a sample to be detected of the linezolid raw material or the linezolid solid preparation or the linezolid liquid preparation is 5-10 mg/mL -1 。
Further, the proportion of the modifier methanol in the mobile phase is 0-40% (v/v). More preferably, it is 20 to 30% (v/v).
Further, the proportion of the modifying agent ethanol in the mobile phase is 0-40% (v/v). More preferably, it is 5 to 15% (v/v).
Further, the volume ratio of methanol to acetonitrile in the modifier methanol-acetonitrile mixed solvent is 100. More preferably, 100.
Furthermore, the active group of the filler of the chromatographic column is cellulose or amylose type chiral stationary liquid, and the column temperature is 25-40 ℃. More preferably, the column temperature of the amylose type chiral stationary liquid is 30-40 ℃.
Furthermore, the sample injection volume of the chromatographic column is 1 to 10 mu L, and the flow rate is 1.0 to 2.5 mL/min -1 . More preferably, the sample introduction volume is 2. Mu.L, and the flow rate is 1.5 mL/min -1 . Other suitable columns may be selected and the flow rate may be adjusted to suit the selected column size. The sample injection volume can be adjusted to a sample injection volume adapted to the sample loading of the chromatographic column or the response of the detector.
Further, the limit of detection of linezolid was about 0.5. Mu.g.mL-1 (about 0.005%).
Example 1
The instruments used in this example were: a Waters Acquity UPCC ultra-high performance phase chromatograph equipped with an ultraviolet detector, a binary gradient pump and an automatic sample injector; electronic balance (ME 235S, sartorius, germany).
Wherein, the chromatographic column used is Waters TrefoilAMY1 (3.0 mm. Times.50mm, 2.5 μm); flow rate: 1.5 mL/min -1 (ii) a Sample introduction volume: 2 mu L of the solution; column temperature: 35 ℃ is carried out.
The mobile phase was carbon dioxide-methanol = 70% (v/v).
Detecting the enantiomer impurities in the raw material (crude product) of linezolid and tablets thereof.
1. Preparation of system suitability solution: appropriate amount of linezolid and its enantiomer as reference are respectively taken, dissolved in methanol and diluted to obtain solutions containing about 0.1mg of linezolid per 1 ml.
2. Preparation of linezolid raw material solution: taking a proper amount of linezolid raw material (the source is A), adding methanol to dissolve and diluting to prepare a solution containing about 10mg in each 1 ml.
3. Preparation of linezolid enantiomer solutions: taking a proper amount of linezolid enantiomer, adding methanol for dissolving and quantitatively diluting to prepare a solution containing about 2 mu g of linezolid per 1 ml.
4. Preparation of linezolid tablet samples: taking a proper amount of fine powder (the sources are B and C respectively, the specification is 600 mg) of the linezolid tablets respectively, adding methanol, carrying out ultrasonic treatment for 20 minutes to dissolve the linezolid, and quantitatively diluting the solution with the methanol to prepare a solution containing 10mg of linezolid in each 1 ml.
According to the above-mentioned instrument and test method, sample analysis is carried out.
The experimental results of the system applicability solution, the linezolid raw material solution and the linezolid tablets from different sources are shown in the figures 1 to 5.
Example 2
The apparatus and chromatographic conditions used in this example were the same as in example 1.
Preparation of linezolid glucose injection solution: weighing 2.5ml of linezolid glucose injection (from A, C-E and containing 2mg/ml of linezolid), adding 5ml of ethyl acetate, 30001 min -1 Vortex 2min, 3000r.min -1 Centrifuging for 10min, extracting for 3 times, mixing ethyl acetate layers, blowing under nitrogen flow, and re-dissolving the dried solid in 0.5ml of methanol.
The sample was analyzed according to the apparatus and test method of example 1. Typical chromatograms are shown in FIGS. 6-9.
Example 3
The apparatus used in this example was the same as in example 1.
Wherein, the chromatographic column used is Waters Trefoil CEL1 (3.0 mm. Times.150mm, 2.5 μm); flow rate: 1.5 mL/min -1 (ii) a Sample introduction volume: 2 mu L of the solution; column temperature: at 25 ℃.
The mobile phase was carbon dioxide-ethanol = 88% (v/v).
Preparation of linezolid and its enantiomer mixed solution: taking appropriate amount of linezolid and enantiomer thereof, precisely weighing, adding methanol for dissolving, and quantitatively diluting to obtain solutions each containing 0.25mg in each 1 ml.
The apparatus of example 1 and the test method described above were followed for sample analysis. A typical chromatogram is shown in FIG. 10.
From the above examples 1 to 3, it can be seen that the supercritical fluid chromatography method established in the present invention can achieve good separation of linezolid and its enantiomers, other impurities in the preparation do not interfere with detection of isomers, and the isomer chromatographic peak is eluted before the linezolid chromatographic peak, which is beneficial to analysis of isomers and preparation and purification of linezolid raw materials. The method is simple and rapid to operate, has high sensitivity, and can provide a good quality control method for linezolid raw materials and preparations thereof.
The embodiment shows that the method for extracting linezolid from the linezolid glucose injection can fully extract and concentrate linezolid and related impurities thereof, solves the problem that an aqueous solution type preparation is difficult to directly determine the enantiomer by adopting a normal phase chromatography, and provides a new idea for quality control of the linezolid glucose injection.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the spirit and scope of the invention.
Claims (8)
1. A separation and analysis method for linezolid and enantiomers in a preparation thereof is characterized in that the detection method is a supercritical fluid chromatography and comprises the following steps:
step 1) dissolving a linezolid raw material by adopting methanol or acetonitrile to obtain a sample to be detected; ultrasonically treating the linezolid solid preparation by using methanol or acetonitrile, centrifuging and filtering to obtain a sample to be detected; after volatilizing the solvent, re-dissolving the linezolid liquid preparation with methanol or acetonitrile to obtain a sample to be detected;
step 2) detecting by using carbon dioxide and a modifier as a mobile phase, a chiral chromatographic column as a stationary phase and an ultraviolet detector;
wherein the modifier is one or more of methanol, ethanol and acetonitrile.
2. The method for separating and analyzing linezolid and enantiomers in the linezolid preparation according to claim 1, wherein the concentration of linezolid in a sample to be tested of a linezolid raw material or a linezolid solid preparation or a linezolid liquid preparation is 5-10 mg-mL -1 。
3. The method for separating and analyzing linezolid and enantiomers thereof according to claim 1 wherein the ratio of modifier methanol in the mobile phase is 0-40% (v/v).
4. The method for separating and analyzing linezolid and enantiomers thereof according to claim 1, wherein the ratio of modifying ethanol in the mobile phase is 0-40% (v/v).
5. The method for separating and analyzing the enantiomers of linezolid and the preparation thereof according to claim 1, wherein the volume ratio of methanol to acetonitrile in the modifier methanol-acetonitrile mixed solvent is from 100.
6. The method for separating and analyzing linezolid and enantiomers thereof according to claim 1, wherein the filler active group of the chromatographic column is a cellulose or amylose type chiral stationary liquid, and the column temperature is 25-40 ℃.
7. The method for separating and analyzing linezolid and enantiomers thereof according to claim 6, wherein the filler active group of the chromatographic column is amylose chiral stationary liquid, and the column temperature is 30-40 ℃.
8. The method for the separation and analysis of enantiomers of linezolid and formulations thereof according to claim 1, wherein the method comprisesThe sample injection volume of the chromatographic column is 1 to 10 mu L, and the flow rate is 1.0 to 2.5 mL/min -1 。
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Citations (8)
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| WO2007116284A1 (en) * | 2006-04-07 | 2007-10-18 | Pfizer Products Inc. | Process for preparing linezolid |
| US20080237130A1 (en) * | 2004-04-07 | 2008-10-02 | Waters Investments Limited | Compositions and Methods for Separating Enantiomers |
| CN101415694A (en) * | 2006-04-07 | 2009-04-22 | 辉瑞产品公司 | Process for preparing linezolid |
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| CN109444294A (en) * | 2018-12-27 | 2019-03-08 | 南京盖斯夫医药科技有限公司 | A kind of efficient liquid-phase chromatography method separating Linezolid and its chiral isomer |
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2022
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| WO2007116284A1 (en) * | 2006-04-07 | 2007-10-18 | Pfizer Products Inc. | Process for preparing linezolid |
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| US20200024278A1 (en) * | 2016-09-30 | 2020-01-23 | Mutabilis | Composition comprising antibiotic compound and an heterocyclic compound and their use in preventing or treating bacterial infections |
| CN107703235A (en) * | 2017-07-18 | 2018-02-16 | 广东研捷医药科技有限公司 | A kind of lenalidomide enantiomter supercritical fluid chromatography separation method |
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