CN111024831A - Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography - Google Patents

Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography Download PDF

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CN111024831A
CN111024831A CN201811180918.3A CN201811180918A CN111024831A CN 111024831 A CN111024831 A CN 111024831A CN 201811180918 A CN201811180918 A CN 201811180918A CN 111024831 A CN111024831 A CN 111024831A
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acid
phase
solution
impurities
moxifloxacin hydrochloride
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朱永强
杜柳辉
宋慧
关众
仲丽茹
杨杨
叶海英
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Jiangsu Chia Tai Fenghai Pharmaceutical Co Ltd
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Abstract

The invention discloses a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography, which takes alkyl bonded silica gel or phenyl bonded silica gel as a filling agent; taking a mixed solution of an aqueous phase and an organic phase as a mobile phase, wherein the aqueous phase is an aqueous solution of a fluorinated organic acid, and the organic phase is methanol or acetonitrile; gradient elution; the method has good specificity, linearity and system durability, can detect A, B, C, D, E, H, I, J impurities and M9 impurities introduced in the synthesis process of moxifloxacin hydrochloride, and has certain practicability.

Description

Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography
Technical Field
The invention relates to a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography.
Background
Moxifloxacin is a novel fourth-generation quinolone representative drug and has a molecular formula C21H24FN3O4Molecular weight 401.44, structural formula:
Figure BDA0001822594140000011
moxifloxacin hydrochloride is an ultra-broad spectrum quinolone anti-infective drug developed by bayer corporation in germany in 1999, and the product is first marketed in germany, approved by FDA in 10.12.1999, under the trade designation "Avelox", and is currently used clinically in many countries and regions of the world. Moxifloxacin eye drops developed by idercongrost in 4 months 2003 were also approved by the FDA for marketing.
The moxifloxacin hydrochloride is usually obtained by directly condensing 1-cyclopropyl-6, 7-difluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinoline carboxylic acid and (S, S) -octahydro-6H-pyrrolo [3,4-b ] pyridine and then purifying, and some process impurities are easily introduced in the synthesis process, and the content of the impurities affects the pharmacodynamic activity on one hand and possibly increases the adverse reaction of the medicament on the other hand, so that the separation of the impurities in the moxifloxacin hydrochloride and the injection thereof has important significance for controlling the quality of the moxifloxacin hydrochloride and the clinical curative effect of the moxifloxacin hydrochloride preparation.
However, in the prior art, the quality control of moxifloxacin hydrochloride is difficult to monitor important impurities one by one, and the quality of moxifloxacin hydrochloride is difficult to evaluate well.
Disclosure of Invention
The invention aims to provide a method for separating moxifloxacin hydrochloride and impurities thereof by using a high performance liquid chromatography. The chromatographic method has good specificity, linearity, precision and system durability, can be used for analyzing and detecting related substances in a moxifloxacin hydrochloride raw material, an injection thereof and a sodium chloride injection thereof, and well separates moxifloxacin and impurities thereof. The invention provides a method for separating moxifloxacin hydrochloride and impurities thereof by using a high performance liquid chromatography, which comprises the following steps:
a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography comprises the following steps:
1) sample preparation:
and (3) testing the sample: dissolving and diluting a proper amount of moxifloxacin hydrochloride or an injection thereof or a sodium chloride injection thereof with a mobile phase to prepare a solution containing 0.5-1.5 mg of moxifloxacin in per 1ml as a test solution;
control solution: taking a proper amount of test solution, and quantitatively diluting with a mobile phase to prepare a 1% control solution;
2) chromatographic conditions are as follows:
stationary phase: the reversed phase chromatographic column takes alkyl bonded silica gel or phenyl bonded silica gel as a filling agent;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is an aqueous solution of a fluorinated organic acid, and the organic phase is methanol or acetonitrile; the gradient elution conditions were as follows:
Figure BDA0001822594140000021
flow rate: 1.0-1.5 ml/min;
column temperature: 40-50 ℃;
detection wavelength: 290-295 nm;
3) and (3) determination: precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
Further, the filler is octadecyl bonded silica gel or pentafluorophenyl bonded silica gel; the concentration of the fluorinated organic acid is 0.001 to 0.05%, preferably 0.002 to 0.01%.
Further, the fluorinated organic acid is one or a mixture of two of trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, nonafluoropentanoic acid, undecafluorohexanoic acid, tridecafluoroheptanoic acid and pentadecafluorooctanoic acid, and preferably the mixture of heptafluorobutyric acid, nonafluoropentanoic acid, trifluoroacetic acid and heptafluorobutyric acid or the mixture of nonafluoropentanoic acid and trifluoroacetic acid; the volume ratio of the trifluoroacetic acid to the heptafluorobutyric acid is 0.5-1: 1; the volume ratio of the nonafluorovaleric acid to the trifluoroacetic acid is 0.5-1: 1.
Further, the gradient elution conditions are:
Figure BDA0001822594140000022
further, the detection wavelength is 293 nm; the column temperature was 45 ℃; the flow rate of the mobile phase was 1.3 ml/min.
The technical scheme provided by the invention can detect 9 impurities introduced in the synthesis process of moxifloxacin hydrochloride, namely the impurity A, B, C, D, E, H, I, J and the impurity M, and the structure of the impurity M is as follows:
impurity A:
Figure BDA0001822594140000031
1-cyclopropyl-7- (S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl) -6, 8-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
Impurity B:
Figure BDA0001822594140000032
1-cyclopropyl-7- (S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl) -6, 8-dimethoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
Impurity C:
Figure BDA0001822594140000033
1-cyclopropyl-7- (S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl) -6-fluoro-8-ethoxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
Impurity D:
Figure BDA0001822594140000034
1-cyclopropyl-7- (S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl) -6-methoxy-8-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
Impurity E:
Figure BDA0001822594140000035
1-cyclopropyl-7- (S, S-2, 8-diazo-bicyclo [4.3.0] nonan-8-yl) -6-fluoro-8-hydroxy-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid
Impurity H:
Figure BDA0001822594140000041
1-cyclopropyl-7- { 2-methyl- (S, S) -2, 8-diazabicyclo [4.3.0] nonan-8-yl } -6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid
Impurity I:
Figure BDA0001822594140000042
1-cyclopropyl-6-fluoro-7-amino-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
Impurity J:
Figure BDA0001822594140000043
1-cyclopropyl-7- { 1-amino-8-azabicyclo [4.3.0] nonan-8-yl } -6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid
Impurity M:
Figure BDA0001822594140000044
1-cyclopropyl-7- { 3-oxo- (S, S) -2, 8-diazabicyclo [4.3.0] nonan-8-yl } -6-fluoro-8-methoxy-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acid
The technical scheme provided by the invention shows the obvious advantages of moxifloxacin hydrochloride and impurity separation thereof. The inventors have methodological verified the chromatographic conditions obtained from the above experiments.
1) Specificity experiments
Positioning test: the moxifloxacin hydrochloride and the mixed solution of 9 known impurities thereof are determined by the method, and the moxifloxacin is well separated from each known impurity.
TABLE 1 results of the positioning test
Figure BDA0001822594140000051
2) Results of the Linear experiment
The concentrations of moxifloxacin and 9 impurities are respectively taken as an X axis, the peak area is taken as a Y axis, and the linear relationship between the concentrations is as follows:
TABLE 2 Standard Curve for moxifloxacin and its various known impurities
Figure BDA0001822594140000052
Figure BDA0001822594140000061
The linear relation between the peak areas and the concentrations of the moxifloxacin and each known impurity is good within the range of the limit concentration of the quantification limit of each component to 120 percent (correlation coefficient R)2≥0.996)。
3) Detection limit, quantitative limit
Diluting each component stock solution until the concentration of each component response and baseline noise S/N is 3 is the detection limit of the component; by response and baseline noise S/N10, the concentration is the quantitative limit for that component. The detection limit and the quantification limit of each known impurity determined by the method are respectively as follows:
TABLE 3 detection and quantitation limits for moxifloxacin and its various known impurities
Figure BDA0001822594140000062
The detection limit and the quantitative limit of each known impurity and moxifloxacin are known, and both the detection limit and the quantitative limit of the method are lower than the concentration of a test sample by 0.01 percent, so that the analysis requirement can be met.
4) System durability test
The flow rate (+ -0.1 ml/min), the column temperature (+ -1 ℃) and the initial proportion (+ -2%) of the mobile phase are properly changed, the mixed solution of the moxifloxacin and each known impurity is measured by adopting the method, the influence of various changes on the separation of the main peak and each impurity is examined, and the result shows that when the certain condition is properly changed, each known impurity and each impurity and the main peak can be effectively separated, and the durability of the method is good.
TABLE 4 System durability test results
Figure BDA0001822594140000071
In conclusion, the chromatographic method has good specificity, linearity and system durability, can detect A, B, C, D, E, H, I, J impurities and M9 impurities introduced in the synthesis process of moxifloxacin hydrochloride, and has certain practicability.
Drawings
FIG. 1: HPLC chromatogram of the detection method described in example 1
FIG. 2: HPLC chromatogram of the detection method described in example 2
Detailed Description
Example 1
Chromatographic conditions are as follows:
mobile phase: the water phase is a 0.01 percent aqueous solution of heptafluorobutyric acid; the organic phase is methanol;
the elution procedure is as follows:
Figure BDA0001822594140000072
a chromatographic column: eclipse XDB phenyl bonded silica gel packed column (0.46cm 25cm,5um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 deg.C
Sample introduction amount: 10 μ l
The experimental steps are as follows:
1) weighing about 10mg of moxifloxacin hydrochloride reference substance, placing the moxifloxacin hydrochloride reference substance into a 10ml measuring flask, adding a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I) to ensure that each ml of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and fixing the volume to a scale by using methanol to obtain a system applicability solution.
2) And injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) And (3) detection results:
the HPLC chromatogram obtained from the detection result is shown in FIG. 1; the retention time and separation of each impurity from moxifloxacin are shown in the following table:
Figure BDA0001822594140000081
example 2
Chromatographic conditions are as follows:
mobile phase: the water phase is a 0.01 percent heptafluorobutyric acid/trifluoroacetic acid mixed solution, wherein the volume ratio of the heptafluorobutyric acid to the trifluoroacetic acid is 2: 1;
the organic phase is acetonitrile;
the elution procedure is as follows:
Figure BDA0001822594140000082
a chromatographic column: pentafluorophenyl bonded silica gel packed column (0.46cm 25cm,5um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 deg.C
Sample introduction amount: 10 μ l
Experimental procedure
1) Weighing 10mg of moxifloxacin hydrochloride reference substance, placing the reference substance into a 10ml measuring flask, adding a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I) to ensure that each ml of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and fixing the volume to a scale by using methanol to obtain a system applicability solution.
2) And injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) And (3) detection results:
the HPLC chromatogram obtained from the detection result is shown in FIG. 2; the retention time and the degree of separation of each impurity from moxifloxacin were as follows:
Figure BDA0001822594140000091
example 3
Chromatographic conditions are as follows:
mobile phase: the water phase is 0.002% of aqueous solution of nonafluorovaleric acid; the organic phase is methanol;
the elution procedure is as follows:
Figure BDA0001822594140000092
a chromatographic column: eclipse XDB phenyl bonded silica gel packed column (0.46cm 25cm,5um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 deg.C
Sample introduction amount: 10 μ l
The experimental steps are as follows:
4) weighing about 10mg of moxifloxacin hydrochloride sodium chloride injection reference substance, placing the reference substance into a 10ml measuring flask, adding a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I)) to ensure that each ml of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and metering to the scale with methanol to obtain a system applicability solution.
2) And injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) And (3) detection results:
the retention time and the degree of separation of each impurity from moxifloxacin were as follows:
Figure BDA0001822594140000093
Figure BDA0001822594140000101
example 4
Chromatographic conditions are as follows:
mobile phase: the water phase is 0.002% of nonafluorovaleric acid/trifluoroacetic acid aqueous solution; wherein the volume ratio of the heptafluorobutyric acid to the trifluoroacetic acid is 1:1, and the organic phase is acetonitrile;
the elution procedure is as follows:
Figure BDA0001822594140000102
a chromatographic column: octadecyl bonded silica gel packed column
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 deg.C
Sample introduction amount: 10 μ l
The experimental steps are as follows:
5) weighing about 10mg of moxifloxacin hydrochloride injection reference substance, placing the reference substance into a 10ml measuring flask, adding a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I) to ensure that each milliliter of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and metering to a scale with methanol to obtain a system applicability solution.
2) And injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) And (3) detection results:
the retention time and the degree of separation of each impurity from moxifloxacin were as follows:
Figure BDA0001822594140000103

Claims (10)

1. a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography is characterized by comprising the following steps:
1) sample preparation:
and (3) testing the sample: dissolving and diluting a proper amount of moxifloxacin hydrochloride or an injection thereof or a sodium chloride injection thereof with a mobile phase to prepare a solution containing 0.5-1.5 mg of moxifloxacin in per 1ml as a test solution;
control solution: taking a proper amount of test solution, and quantitatively diluting with a mobile phase to prepare a 1% control solution;
2) chromatographic conditions are as follows:
stationary phase: the reversed phase chromatographic column takes alkyl bonded silica gel or phenyl bonded silica gel as a filling agent;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is an aqueous solution of a fluorinated organic acid, and the organic phase is methanol or acetonitrile; the gradient elution conditions were as follows:
Figure FDA0001822594130000011
flow rate: 1.0-1.5 ml/min;
column temperature: 40-50 ℃;
detection wavelength: 290-295 nm;
3) and (3) determination: precisely measuring 10 μ l of each of the test solution and the control solution, respectively injecting into a liquid chromatograph, and recording chromatogram.
2. The method of claim 1, wherein the filler is octadecyl-bonded silica gel or pentafluorophenyl-bonded silica gel.
3. The process according to claim 1, characterized in that the concentration of the fluorinated organic acid is between 0.001 and 0.05%, preferably between 0.002 and 0.01%.
4. A process according to any one of claims 1 to 3, characterised in that the fluorinated organic acid is any one of or a mixture of two of trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, nonafluoropentanoic acid, undecafluorohexanoic acid, tridecafluoroheptanoic acid, pentadecafluorooctanoic acid.
5. The process according to claim 4, characterized in that the fluorinated organic acid is selected from heptafluorobutyric acid, nonafluorovaleric acid, a mixture of trifluoroacetic acid and heptafluorobutyric acid or a mixture of nonafluorovaleric acid and trifluoroacetic acid.
6. The method according to claim 5, wherein the volume ratio of trifluoroacetic acid to heptafluorobutyric acid is 0.5-1: 1; the volume ratio of the nonafluorovaleric acid to the trifluoroacetic acid is 0.5-1: 1.
7. The method according to claim 1, characterized in that the gradient elution conditions are:
Figure FDA0001822594130000021
。
8. the method of claim 1, wherein the detection wavelength is 293 nm.
9. The process according to claim 1, wherein the column temperature is 45 ℃.
10. The method of claim 1, wherein the mobile phase flow rate is 1.3 ml/min.
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CN115598267A (en) * 2022-12-13 2023-01-13 山东省食品药品检验研究院（Cn） Analysis method of potential genotoxic impurities in gliclazide

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