CN111024831B - 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 PDFInfo
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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 bonding silica gel or phenyl bonding silica gel as a filler; 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 fluoro-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
Technical Field
The invention relates to a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography.
Background
Moxifloxacin is the latest fourth-generation quinolone representative drug, and the molecular formula is C 21 H 24 FN 3 O 4 Molecular weight 401.44, structural formula as follows:
moxifloxacin hydrochloride is an ultra-broad-spectrum quinolone anti-infective drug developed by bayer corporation in germany in 1999, which was first marketed in germany, approved by the FDA on 12 th month 10 1999 under the trade name "Avelox", and is currently used clinically in many countries and regions of the world. Moxifloxacin eye drops developed by ai kang were also approved by the FDA for marketing 4 months 2003.
The moxifloxacin hydrochloride is generally 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 purifying the same, wherein some process impurities are easy to introduce in the synthesis process, the impurity content affects the pharmacodynamic activity on one hand, and the adverse reaction of the medicine is possibly increased on the other hand, so that the impurity separation 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 generally difficult to monitor important impurities of moxifloxacin hydrochloride one by one, and the quality of moxifloxacin hydrochloride is difficult to well evaluate.
Disclosure of Invention
The invention aims to provide a method for separating moxifloxacin hydrochloride and impurities thereof by 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 moxifloxacin hydrochloride raw materials, injection and sodium chloride injection, and well separates moxifloxacin and impurities thereof. The invention provides a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography, which comprises the following steps:
a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography, comprising the following steps:
1) Sample preparation:
test article: taking a proper amount of moxifloxacin hydrochloride or an injection thereof or sodium chloride injection thereof, adding a mobile phase for dissolution and dilution to prepare a solution containing 0.5-1.5 mg of moxifloxacin in each 1ml as a test solution;
control solution: taking a proper amount of sample solution, quantitatively diluting with a mobile phase, and preparing a 1% control solution;
2) Chromatographic conditions:
stationary phase: reversed phase chromatographic column with alkyl bonded silica gel or phenyl bonded silica gel as filler;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is an aqueous solution of fluoro organic acid, and the organic phase is methanol or acetonitrile; gradient elution conditions were as follows:
flow rate: 1.0-1.5 ml/min;
column temperature: 40-50 ℃;
detection wavelength: 290-295 nm;
3) And (3) measuring: precisely measuring 10 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms.
Further, the filler is octadecyl bonded silica gel or pentafluorophenyl bonded silica gel; the concentration of the fluoroorganic acid is 0.001-0.05%, preferably 0.002-0.01%.
Further, the fluorinated organic acid is any one or two of trifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid, nonafluoropentanoic acid, undecanoic acid, tridecanfluoroheptanoic acid and pentadecafluorooctanoic acid, preferably heptafluorobutyric acid, nonafluoropentanoic acid, a mixture of trifluoroacetic acid and heptafluorobutyric acid or a 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:
further, the detection wavelength is 293nm; the column temperature is 45 ℃; the mobile phase flow rate was 1.3ml/min.
The technical scheme provided by the invention can detect 9 impurities which are respectively impurity A, B, C, D, E, H, I, J and impurity M and are introduced in the synthesis process of moxifloxacin hydrochloride, and has the following structure:
impurity A:
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:
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:
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:
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:
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:
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:
1-cyclopropyl-6-fluoro-7-amino-8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid
Impurity J:
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:
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 obvious advantages in the aspects of separating moxifloxacin hydrochloride and impurities thereof. The inventors performed methodological validation of 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 measured according to the method, and the moxifloxacin is well separated from each known impurity.
TABLE 1 positioning test results
2) Results of the Linear experiments
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 two is as follows:
TABLE 2 Standard curves for Moxifloxacin and its known impurities
Within the range of limiting the concentration of each component to 120 percentThe peak area of each known impurity of moxifloxacin has a good linear relationship with the concentration (correlation coefficient R 2 ≥0.996)。
3) Limit of detection and limit of quantification
Diluting each component stock solution until the concentration of each component response and baseline noise S/n=3 is the component detection limit; by the time response and baseline noise S/n=10, its concentration is the component limit. The detection limit and the quantitative limit of each known impurity are respectively as follows:
TABLE 3 detection limit and quantification limit of Moxifloxacin and its known impurities
The detection limit and the quantitative limit of each known impurity and moxifloxacin are lower than the detection limit and the quantitative limit of the test sample concentration by 0.01%, so that the analysis requirement can be met.
4) System durability experiment
The mixed solution of moxifloxacin and each known impurity was measured by the above method by appropriately changing the flow rate (+ -0.1 ml/min), the column temperature (+ -1 ℃) and the initial proportion (+ -2%) of the mobile phase, and the influence of various changes on the separation of the main peak and each impurity was examined, and the results showed that the separation between each known impurity and between the impurity and the main peak was effective when the above-mentioned certain conditions were appropriately changed, indicating that the durability of the method was good.
Table 4 results of durability test of system
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 moxifloxacin hydrochloride synthesis process, 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:
mobile phase: the water phase is 0.01% of heptafluorobutyric acid water solution; the organic phase is methanol;
the elution procedure is as follows:
chromatographic column: eclipse XDB phenyl bonded silica gel packed column (0.46 cm. Times.25cm, 5 um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 DEG C
Sample injection amount: 10 μl of
The experimental steps are as follows:
1) About 10mg of moxifloxacin hydrochloride reference substance is weighed, placed in a 10ml measuring flask, and added with a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I), so that each milliliter of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and methanol is used for fixing the volume to the scale to be used as a system applicability solution.
2) And (5) injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) Detection result:
the HPLC chromatogram obtained by the detection result is shown in figure 1; the retention time and the separation degree of each impurity and moxifloxacin are shown in the following table:
example 2
Chromatographic conditions:
mobile phase: the water phase is 0.01% of mixed solution of heptafluorobutyric acid and trifluoroacetic acid, 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:
chromatographic column: pentafluorophenyl bonded silica gel packed column (0.46 cm. Times.25cm, 5 um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 DEG C
Sample injection amount: 10 μl of
Experimental procedure
1) The moxifloxacin hydrochloride reference substance 10mg is weighed, placed in a 10ml measuring flask, and added with a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I), so that each milliliter of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and methanol is used for fixing the volume to the scale to be used as a system applicability solution.
2) And (5) injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) Detection result:
the HPLC chromatogram obtained by the detection result is shown in figure 2; the retention time and the separation degree of each impurity and moxifloxacin are as follows:
example 3
Chromatographic conditions:
mobile phase: the aqueous phase is 0.002% of nonafluorovaleric acid aqueous solution; the organic phase is methanol;
the elution procedure is as follows:
chromatographic column: eclipse XDB phenyl bonded silica gel packed column (0.46 cm. Times.25cm, 5 um)
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 DEG C
Sample injection amount: 10 μl of
The experimental steps are as follows:
4) About 10mg of moxifloxacin hydrochloride sodium chloride injection reference is weighed, placed in a 10ml measuring flask, and a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I) is added, so that each impurity in each ml of mixed solution is 1ug, each impurity in each ml of mixed solution is 1mg, and methanol is used for fixing the volume to the scale, so that the mixed solution is used as a system applicability solution.
2) And (5) injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) Detection result:
the retention time and the separation degree of each impurity and moxifloxacin are as follows:
example 4
Chromatographic conditions:
mobile phase: the aqueous phase is 0.002% of an aqueous solution of nonafluorovaleric acid/trifluoroacetic acid; 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:
chromatographic column: octadecyl bonded silica gel packed column
Detection wavelength: 293nm
Flow rate: 1.3ml/min
Column temperature: 45 DEG C
Sample injection amount: 10 μl of
The experimental steps are as follows:
5) About 10mg of moxifloxacin hydrochloride injection reference is weighed, placed in a 10ml measuring flask, and a proper amount of each impurity stock solution (impurity M, H, A, B, C, D, E, J, I) is added, so that each milliliter of mixed solution contains 1ug of each impurity and 1mg of moxifloxacin hydrochloride, and methanol is used for fixing the volume to the scale to be used as a system applicability solution.
2) And (5) injecting the system applicability solution into a liquid chromatograph, and recording the detection result.
3) Detection result:
the retention time and the separation degree of each impurity and moxifloxacin are as follows:
Claims (6)
1. a method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography, which is characterized by comprising the following steps:
1) Sample preparation:
test article: taking a proper amount of moxifloxacin hydrochloride or injection thereof, adding a mobile phase for dissolution and dilution to prepare a solution containing 0.5-1.5 mg of moxifloxacin in each 1ml as a test solution;
control solution: taking a proper amount of sample solution, quantitatively diluting with a mobile phase, and preparing a 1% control solution;
2) Chromatographic conditions:
chromatographic column: eclipse XDB phenyl-bonded silica gel packed column;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is a heptafluorobutyric acid aqueous solution, and the organic phase is methanol; gradient elution conditions were as follows:
or a chromatographic column: a pentafluorophenyl bonded silica gel packed column;
mobile phase: the mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is an aqueous solution of mixed heptafluorobutyric acid and trifluoroacetic acid, the volume ratio of the heptafluorobutyric acid to the trifluoroacetic acid is 2:1, and the organic phase is acetonitrile; gradient elution conditions were as follows:
or a chromatographic column: eclipse XDB phenyl-bonded silica gel packed column;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is an aqueous solution of nonafluorovaleric acid, and the organic phase is methanol; gradient elution conditions were as follows:
or a chromatographic column: octadecyl bonded silica gel packed column;
mobile phase: a mixed solution of an aqueous phase and an organic phase, wherein the aqueous phase is a mixed aqueous solution of nonafluorovaleric acid and trifluoroacetic acid, the volume ratio of the nonafluorovaleric acid to the trifluoroacetic acid is 1:1, and the organic phase is acetonitrile; gradient elution conditions were as follows:
flow rate: 1.0-1.5 ml/min;
column temperature: 40-50 ℃;
detection wavelength: 290-295 nm;
3) And (3) measuring: precisely measuring 10 μl of each of the sample solution and the control solution, respectively injecting into a liquid chromatograph, and recording the chromatograms; the impurities are as follows:
impurity A:
impurity B:
impurity C:
impurity D:
impurity E:
impurity H:
impurity I:
/>
impurity J:
impurity M:
2. the method of claim 1, wherein the concentration of acid in the mobile phase aqueous phase is 0.001-0.05%.
3. The process according to claim 1 or 2, characterized in that the concentration of acid in the mobile phase aqueous phase is 0.002-0.01%.
4. The method according to claim 1, characterized in that the detection wavelength is 293nm.
5. The method according to claim 1, wherein the column temperature is 45 ℃.
6. The method according to claim 1, wherein the mobile phase flow rate is 1.3ml/min.
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