CN114113353A - Method for separating and detecting ethyl gatifloxacin and/or related impurities - Google Patents
Method for separating and detecting ethyl gatifloxacin and/or related impurities Download PDFInfo
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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
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
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- 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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- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
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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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Abstract
The invention relates to the technical field of drug analysis, in particular to a method for analyzing ethyl gaboxylate and related impurities by using a high performance liquid chromatography. The chromatographic column adopted by the method is a phenyl bonded silica gel filler, and is subjected to gradient elution by adopting a buffer salt solution and an organic solvent, wherein the flow rate is 0.9-1.1 ml/min, and the column temperature is 23-27 ℃. The analysis method provided by the invention can well separate and accurately quantify the impurities MOXH-SM1f and MOXH-SM1i with the structure highly similar to that of the ethyl gaboxylate within 37 minutes, and can effectively separate the impurities from other 7 known impurities possibly existing in the ethyl gaboxylate, thereby providing the problem of separation and determination of the known impurities in the ethyl gaboxylate which cannot be solved by the prior art.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to a method for analyzing ethyl gaboxylate and related impurities by using a high performance liquid chromatography.
Background
Moxifloxacin is a nearly white crystalline powder chemical with the molecular formula C21H24FN3O4Fluoroquinolones as antibacterial agents. The DNA topoisomerase inhibitor can be used for treating social pneumonia, acute episode of chronic bronchitis, acute sinusitis and the like caused by staphylococcus aureus, bacillus influenzae, pneumococcus and the like. Belongs to fourth generation quinolone antibacterial drugs, and is a new generation antibiotic with wide antibacterial spectrum. The product has strong antibacterial activity against common respiratory tract bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and part of Staphylococcus aureus, especially against Streptococcus pneumoniae. The traditional Chinese medicine composition is clinically used for treating acute sinusitis, acute attack of chronic bronchitis, community-acquired pneumonia, and skin infection and skin soft tissue infection without complications. The product has the characteristics of almost no photosensitive reaction, good tissue penetrating power and high concentration in lung tissues, and is a good medicament for treating respiratory tract infection.
The ethyl gatifloxacin carboxylate is a key starting material of moxifloxacin, and the quality control of the ethyl gatifloxacin carboxylate is favorable for guaranteeing the quality of moxifloxacin medicaments. According to the known impurity structural formula possibly contained in the finished product in the quality standard of Moxifloxacin hydrochloride EP10.3 pharmacopoeia, the following 2 impurities with a structure highly similar to that of the ethyl gaboxylate probably exist in the raw material ethyl gaboxylate:
at present, no relevant documents or data disclose a method for separating and detecting the two impurities.
Disclosure of Invention
In view of the above, it is an object of the present invention to provide a method for separating ethyl gaboxylate and/or related impurities by HPLC, by which related substances can be efficiently separated and separation time can be reduced.
In order to achieve the purpose, the scheme provided by the invention is as follows:
the method for separating the ethyl gaboxylate and/or the related impurities by the HPLC method comprises the following steps of using phenyl bonded silica gel as a filler, performing gradient elution by using a mobile phase A and a mobile phase B, and separating the ethyl gaboxylate and/or the related impurities; the related impurities are one or more of impurities MOXH-SM1a, impurities MOXH-SM1b, impurities MOXH-SM1e, impurities MOXH-SM1m, impurities MOXH-SM1g, impurities MOXH-SM1h, impurities MOXH-SM1j, impurities MOXH-SM1f and impurities MOXH-SM1 i; the structural formula of the ethyl gatifloxacin carboxylate and related impurities is as follows:
the mobile phase A is a buffer salt solution, and the mobile phase B is an organic solvent;
further, the buffer salt solution is a mixed solution of potassium dihydrogen phosphate solution and triethylamine, and the pH value of the buffer salt solution is 2.8-3.2;
specifically, the pH of the buffered salt solution is 3.0;
specifically, the buffered saline solution is adjusted in pH by using phosphoric acid;
further, the concentration of the potassium dihydrogen phosphate in the buffer salt solution is 0.005-0.05 mol/L, and the volume percentage of the triethylamine in the buffer salt solution is 0.05-5.0%.
Specifically, the mass concentration of potassium dihydrogen phosphate in the buffered salt solution is 2.72g/L, and the volume percentage of triethylamine in the buffered salt solution is 0.3%;
further, the organic solvent is one or more of methanol, ethanol and acetonitrile;
specifically, the organic solvent is methanol;
further, the gradient elution is:
time/minute | Mobile phase A/%) | Mobile phase B/%) |
0 | 38-42 | 58-62 |
3 | 40 | 60 |
20 | 30 | 70 |
23 | 20 | 80 |
29 | 20 | 80 |
30 | 40 | 60 |
37 | 40 | 60 |
;
Specifically, the gradient elution is as follows:
time/minute | Mobile phase A/%) | Mobile phase B/%) |
0 | 40 | 60 |
3 | 40 | 60 |
20 | 30 | 70 |
23 | 20 | 80 |
29 | 20 | 80 |
30 | 40 | 60 |
37 | 40 | 60 |
;
Further, the flow velocity of the mobile phase in the method is 0.9-1.1 ml/min; in the method, the temperature of a chromatographic column is 23-27 ℃;
specifically, the flow rate of the mobile phase in the method is 1.0 ml/min; in the method, the column temperature of the chromatographic column is 25 ℃.
The invention also aims to provide a method for identifying the ethyl gaboxylate and/or related impurities, which can effectively identify related substances and reduce the identification time;
in order to achieve the purpose, the scheme provided by the invention is as follows:
the method for identifying the ethyl gaboxylate and/or the related impurities by the HPLC method comprises the steps of separating the ethyl gaboxylate and the related impurities by the method in the first aim, introducing the ethyl gaboxylate and the related impurities into a detector for detection, wherein the detection wavelength of the detector is 210-340 nm; the related impurities are the related impurities in the first aim; comparing the detected chromatogram with a known reference chromatogram, and identifying whether the detected substance contains the ethyl gaboxylate and/or related impurities;
specifically, the detection wavelength of the detector is 250 nm.
The invention also aims to provide a method for determining ethyl gaboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i by using HPLC method; the method can effectively determine the content of related substances and control the determination time;
in order to achieve the purpose, the scheme provided by the invention is as follows:
the method for measuring ethyl gatifloxacin carboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i by an HPLC method comprises the steps of separating ethyl gatifloxacin carboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i by the method in the first objective, detecting in a detector with the detection wavelength of 250nm to obtain a chromatogram, and calculating the content of ethyl gatifloxacin carboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i according to peak areas;
specifically, the method comprises the following specific steps:
s1: reagent preparation
Dissolving a test sample in a diluent to obtain a test sample solution; dissolving a reference substance in a diluent to obtain a reference substance solution; putting the sample into a sample injection disc with the temperature controlled at 2-8 ℃;
s2: separation of
Separating the ethyl gaboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1i using the method described in objective one;
s3: identification
Identifying whether the test substance contains the ethyl gaboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1i by using the method in the second aim;
s4: content calculation
Measuring peak areas according to the obtained chromatogram, and calculating the content of the ethyl gatifloxacin carboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1 i;
further, the diluent is water and acetonitrile;
specifically, the diluent is water and acetonitrile in a volume ratio of 1: 1.
The invention has the beneficial effects that:
1. the analysis method provided by the invention can well separate and detect impurities MOXH-SM1f and MOXH-SM1i which are highly similar to the structure of the ethyl gaboxylate.
2. The main components of the analysis method and other known impurities possibly existing in a sample, the separation degree between the impurity MOXH-SM1f and the impurity MOXH-SM1i is more than 1.5, and the method has the advantages of strong specificity, good durability, high sensitivity and good reproducibility.
3. The analysis method provided by the invention can well separate and accurately quantify the impurities MOXH-SM1f and MOXH-SM1i with the structure highly similar to that of the ethyl gaboxylate within 37 minutes, and can effectively separate the impurities from other 7 known impurities possibly existing in the ethyl gaboxylate, thereby providing the problem of separation and determination of the known impurities in the ethyl gaboxylate which cannot be solved by the prior art.
Drawings
FIG. 1: mixed solution HPLC chromatogram;
FIG. 2: detection limit HPLC chromatogram;
FIG. 3: durability 1HPLC chromatogram;
FIG. 4: durability 2HPLC chromatogram;
FIG. 5: durability 3HPLC chromatogram;
FIG. 6: durability 4HPLC chromatogram;
FIG. 7: durability 5HPLC chromatogram;
FIG. 8: durability 6HPLC chromatogram;
FIG. 9: durability 7HPLC chromatogram;
FIG. 10: durability 8HPLC chromatogram.
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 in light of the above teachings and remain within the scope of the invention.
Example 1
Taking a proper amount of the product, precisely weighing, adding a diluent (water-acetonitrile with the volume ratio of 1:1) for dissolving, quantitatively diluting to prepare a solution containing 1mg of the product in 1ml, taking the solution as a test solution, and immediately placing the prepared solution into a sample injection tray with the temperature controlled at 5 ℃; precisely measuring 5.0ml, placing in a 50ml measuring flask, diluting with diluent to scale, shaking, precisely measuring 2.0ml, placing in a 100ml measuring flask, diluting with diluent to scale, and shaking to obtain control solution.
A column (4.6 mm. times.250 mm, 5 μm) packed with phenyl-bonded silica gel; taking buffer salt (weighing 2.72g of monopotassium phosphate, adding 1000ml of water for dissolution, adding 3.0ml of triethylamine, adjusting pH to 3.0 by using phosphoric acid) as a mobile phase A, taking methanol as a mobile phase B, performing linear gradient elution according to the table 1, and detecting the wavelength to be 250 nm; the flow rate was 1.0ml per minute; the column temperature was 25 ℃.
TABLE 1 gradient elution Table
Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
0 | 40 | 60 |
3 | 40 | 60 |
20 | 30 | 70 |
23 | 20 | 80 |
29 | 20 | 80 |
30 | 40 | 60 |
37 | 40 | 60 |
Accurately weighing a proper amount of a system applicability reference substance 1 (containing ethyl carboxylate MOXH-SM1, impurities MOXH-SM1i and impurities MOXH-SM1f) of the ethyl carboxylate gazette, accurately weighing, adding a diluent to dissolve and dilute the ethyl carboxylate gazette into a solution containing about 1mg in each 1ml, shaking up the solution to be used as a system applicability solution, and immediately putting the solution into a sample injector with the temperature controlled at 5 ℃ after preparation. Injecting 10 mu l of the mixture into a liquid chromatograph, recording a chromatogram, and sequentially generating peaks according to impurities MOXH-SM1f, MOXH-SM1 and MOXH-SM1i, wherein the separation degree between the impurities MOXH-SM1f and the main component meets the requirement. Precisely measuring 10 μ l of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram. The contents of the two impurities are calculated according to a main component comparison method added with a correction factor.
Example 2
Specificity
Replacing impurities possibly present in ethyl carboxylate SM 1: 9 impurities including an impurity MOXH-SM1a, an impurity MOXH-SM1b, an impurity MOXH-SM1e, an impurity MOXH-SM1m, an impurity MOXH-SM1g, an impurity MOXH-SM1h, an impurity MOXH-SM1j, an impurity MOXH-SM1f and an impurity MOXH-SM1i are counted, and the impurities MOXH-SM1f and the impurity MOXH-SM1i are researched in the method.
Respectively taking 10 μ l of blank solution, impurity positioning solution, other impurity mixed solution, sample solution, and mixed solution, sequentially sampling, recording chromatogram, and determining results shown in tables 2 and 3, and figure 1.
TABLE 2HPLC chromatogram integration results for mixed solutions
TABLE 3 results of the specificity test
And (4) conclusion: blank solution and sample solutionDo not interfere with impurities MOXH-SM1fAnd impurity MOXH-SM1iThe main component and other known impurities and impurities MOXH-SM which may be present in the sample1fAnd impurity MOXH-SM1iThe separation degrees between the two are all larger than 1.5, and the specificity of the method meets the requirement.
Example 3
Detection limit
And continuously injecting the detection limit solution for 3 times, and calculating the ratio (signal-to-noise ratio) of the main peak height to the noise. The test results are shown in tables 4 and 5 and FIG. 2.
TABLE 4 integration results of detection limit HPLC chromatograms
TABLE 5 measurement results of detection limits
And (4) conclusion: the detection limit concentration of the impurity MOXH-SM1f is 0.074 mug/ml, which is expressed by the existence concentration in the test sample as 0.007%, and the mean value of the signal-to-noise ratio is 14.2; the detection limit concentration of the impurity MOXH-SM1i is 0.065 mug/ml, the concentration existing in the test sample is expressed as 0.007%, and the mean value of the signal to noise ratio is 10.9; the detection limit concentration of the main component SM1 is 0.064 mug/ml, the concentration of the main component SM1 existing in a test sample is expressed as 0.006%, and the average value of signal-to-noise ratio is 8.4, which all meet the requirement of the detection limit.
Example 4
Durability of chromatographic conditions
Taking the mixed solution under the 'special' item, respectively testing the mixed solution by using normal chromatographic conditions and presetting different tested column temperatures, column flow rates, the initial proportion of mobile phase B phase methanol and the pH value of mobile phase A phase buffer salt, respectively testing after an instrument system is stable, recording the separation degree among all peaks, and inspecting the relative retention time and the normalized content change condition of all known impurities. The test results are shown in tables 2, 6-14, FIG. 1, and FIGS. 3-10 below.
TABLE 6 durability 1HPLC chromatogram integration results
TABLE 7 durability 2HPLC chromatogram integration results
TABLE 8 durability 3HPLC chromatogram integration results
TABLE 9 durability 4HPLC chromatogram integration results
TABLE 10 durability 5HPLC chromatogram integration results
TABLE 11 durability 6HPLC chromatogram integration results
TABLE 12 durability 7HPLC chromatogram integration results
TABLE 13 durability 8HPLC chromatogram integration results
TABLE 14 durability test results for chromatographic condition changes
And (4) conclusion: when the chromatographic conditions have small fluctuation, the separation degree between the impurity MOXH-SM1f and the main peak is more than 1.5, the separation degree between the impurity MOXH-SM1i and the adjacent component is more than 1.4, and the durability of the method is better.
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 to 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 (10)
- The method for separating the ethyl gaboxylate and/or the related impurities by the HPLC method is characterized in that a chromatographic column adopted by the method takes phenyl bonded silica gel as a filler, and adopts a mobile phase A and a mobile phase B for gradient elution to separate the ethyl gaboxylate and/or the related impurities; the related impurities are one or more of impurities MOXH-SM1a, impurities MOXH-SM1b, impurities MOXH-SM1e, impurities MOXH-SM1m, impurities MOXH-SM1g, impurities MOXH-SM1h, impurities MOXH-SM1j, impurities MOXH-SM1f and impurities MOXH-SM1 i; the structural formula of the ethyl gatifloxacin carboxylate and related impurities is as follows:the mobile phase A is a buffer salt solution, and the mobile phase B is an organic solvent.
- 2. The method according to claim 1, wherein the buffered salt solution is a mixed solution of potassium dihydrogen phosphate solution and triethylamine, and the pH of the buffered salt solution is 2.8-3.2.
- 3. The method as claimed in claim 1, wherein the mass concentration of potassium dihydrogen phosphate in the buffered salt solution is 0.005-0.05 mol/L, and the volume percentage of triethylamine in the buffered salt solution is 0.05-5.0%.
- 4. The method of claim 1, wherein the organic solvent is one or more of methanol, ethanol, and acetonitrile.
- 5. The method according to claim 1, wherein the gradient elution is in particular:
time/minute Mobile phase A/%) Mobile phase B/%) 0 38-42 58-62 3 40 60 20 30 70 23 20 80 29 20 80 30 40 60 37 40 60 。 - 6. The method according to claim 1, wherein the flow rate of the mobile phase in the method is 0.9-1.1 ml/min; in the method, the temperature of a chromatographic column is 23-27 ℃.
- The method for identifying the ethyl gaboxylate and/or the related impurities by the HPLC method is characterized in that the ethyl gaboxylate and the related impurities are separated by the method in claim 1 and are introduced into a detector for detection, and the detection wavelength of the detector is 210-340 nm; the relevant impurities are the relevant impurities in claim 1; and comparing the chromatogram obtained by detection with the chromatogram of a known reference substance, and identifying whether the detected substance contains the ethyl gaboxylate and/or related impurities.
- Method for determining ethyl gaboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i by HPLC method, characterized in that the method in claim 1 is used to separate the ethyl gaboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i, a chromatogram is obtained by detecting in a detector with a detection wavelength of 250nm, and the content of the ethyl gaboxylate and/or impurity MOXH-SM1f and/or impurity MOXH-SM1i is calculated according to peak area.
- 9. The method according to claim 8, characterized in that the method comprises the following specific steps:s1: reagent preparationDissolving a test sample in a diluent to obtain a test sample solution; dissolving a reference substance in a diluent to obtain a reference substance solution; putting the prepared reagent into a sample injection disc with the temperature controlled at 2-8 ℃;s2: separation ofSeparating the ethyl gaboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1i using the process as claimed in claim 1;s3: identificationIdentifying whether the assay comprises said ethyl gaboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1i using the method of claim 7;s4: content calculationAccording to the obtained chromatogram, measuring peak areas, and calculating the content of the ethyl gatifloxacin carboxylate and/or the impurity MOXH-SM1f and/or the impurity MOXH-SM1 i.
- 10. The method of claim 9, wherein the diluent is water and acetonitrile.
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