CN109725074B - Method for separating and measuring related substances contained in loxoprofen acid and salt thereof - Google Patents
Method for separating and measuring related substances contained in loxoprofen acid and salt thereof Download PDFInfo
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Abstract
The invention provides a separation and determination method of related substances contained in loxoprofen acid and salts thereof, which comprises the following steps: injecting loxoprofen acid and salt samples thereof into a liquid chromatograph for separation detection; wherein, the chromatographic column of the liquid chromatograph is a C8-C18 column, and the mobile phase is a mixture of water phase and organic phase in a certain proportion. The method can realize quantitative and qualitative determination of related substances contained in the loxoprofen acid and the loxoprofen salt, thereby effectively controlling the quality of the loxoprofen acid and the loxoprofen salt, more effectively realizing quality monitoring of loxoprofen acid and loxoprofen salt products, and having practical guiding significance for improving the quality of related products.
Description
Technical Field
The invention relates to the field of quality control of loxoprofen acid and salts thereof, in particular to a separation and determination method of related substances contained in loxoprofen acid and salts thereof.
Background
Loxoprofen acid and its salt can be used for treating rheumatoid arthritis, osteoarthritis, lumbago, scapulohumeral periarthritis, cervical, shoulder and wrist syndrome, toothache, postoperative pain, trauma, and tooth extraction, and acute upper airway inflammation. The most common of loxoprofen and its salts is loxoprofen sodium, with the chemical name 2- [4- (2-oxocyclopentan-1-ylmethyl) phenyl]Sodium propionate dihydrate of formula C15H17NaO3.2H2And O. The structural formula of the loxoprofen sodium is as follows:
in the process of synthesizing the compound, several important intermediates may affect the purity and quality of the medicine due to incomplete removal; the degradation impurities are generated in the production or storage process of the medicament, have no treatment effect or influence on the stability and curative effect of the medicament, and even harm to human health, and the number of related substances mainly controlling the synthesis and degradation of the loxoprofen and the salt thereof is 5, and the number of the related substances is respectively as follows: ibuprofen related impurities, ibuprofen impurity K, loxoprofen open-loop impurities, loxoprofen related impurities 4 and loxoprofen related impurities 3, wherein the structural formulas are respectively as follows:
the quality control of raw material medicines is required for relevant substances introduced in the process of synthesizing the loxoprofen sodium and degradation impurities in the storage process, so that the separation of the loxoprofen sodium and the relevant substances is realized, and the method has important significance in the quality control of the loxoprofen sodium synthesis and storage processes, but at present, no effective method exists in the prior art in the quality monitoring aspect.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a separation and determination method for related substances contained in loxoprofen acid and salts thereof, which can realize quantitative and qualitative determination of the related substances contained in the loxoprofen acid and the salts thereof, thereby effectively controlling the quality of the loxoprofen acid and the salts thereof, more effectively realizing quality monitoring on loxoprofen acid and the salts thereof, ensuring the purity of the loxoprofen acid and the salts thereof related products, and having practical guiding significance for improving the quality of the related products.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
the embodiment of the invention provides a separation and determination method for related substances contained in loxoprofen acid and salts thereof, which comprises the following steps:
injecting the loxoprofen acid and salt sample solution thereof into a liquid chromatograph for separation and detection;
wherein the chromatographic column of the liquid chromatograph is a C8-C18 column or a T3 column, and the mobile phase is a mixture of an aqueous phase and an organic phase.
The invention provides a method for separating and measuring loxoprofen acid and loxoprofen salt medicines or related substances contained in a preparation thereof by adopting a liquid chromatograph, and realizes effective quality detection of the loxoprofen acid and the loxoprofen salt medicines or the loxoprofen salt preparations by groping specific operation parameters in the measuring method process, provides a very effective monitoring method, and also provides a referable technical route for subsequent operation.
Preferably, the solvent in the sample solution of the loxoprofen acid and the salt thereof is methanol, a mobile phase or a diluent, and the diluent is a mixture of an aqueous phase and an organic phase;
preferably, the loxoprofen acid and the salt thereof are one or a mixture of two of loxoprofen metal salt and loxoprofen acid ammonium salt.
Preferably, as a further implementable manner, the organic phase is a mixture of any one or more of methanol, acetonitrile, propanol, isopropanol, tetrahydrofuran, preferably methanol and acetonitrile, more preferably methanol.
Preferably, as a further implementable manner, the aqueous phase is a mixture of water and any one or more of triethylamine, diethylamine, glacial acetic acid, ammonium acetate, acetate salts, preferably triethylamine and glacial acetic acid, more preferably glacial acetic acid.
In the separation and determination method, the mobile phase and the diluent are both composed of an inorganic phase and a water phase, the loxoprofen acid and the salt sample thereof can be diluted and dissolved by adopting methanol, the diluent or the mobile phase to form a sample solution, the adopted chromatographic column is preferably a C18 column or a T3 column, the separation effect is good, and a T3 column is optimally selected.
Preferably, the loxoprofen acid and the salt thereof in the sample solution of loxoprofen acid and the salt thereof formed above are contained in a concentration of 0.1 to 3mg/ml, more preferably 2 mg/ml.
Preferably, as a further implementable way, the flow rate of the mobile phase is between 0.5 and 2.0ml/min, more preferably 1.0 ml/min.
Preferably, as a further practicable mode, the detection wavelength of the liquid chromatograph is between 200 and 250nm, and the column temperature is between 20 and 40 ℃.
More preferably, the optimal detection wavelength of the liquid chromatograph is 235nm, and the optimal temperature of the column oven is 35 ℃.
Preferably, as a further implementable manner, the sample solution of loxoprofen acid and salt thereof has a sample injection volume of between 10 and 30. mu.L, preferably 20. mu.L.
Preferably, as a further practicable mode, in the diluent, the organic phase is methanol, the aqueous phase is a mixture of water, glacial acetic acid and triethylamine, and the volume ratio of the water, the glacial acetic acid and the triethylamine is (900-: (1-2): (1-2), the volume ratio of the organic phase to the aqueous phase is (30-50): (50-70);
preferably, the volume ratio of the water to the glacial acetic acid to the triethylamine is 1000:2: 1;
preferably, the volume ratio of the organic phase to the aqueous phase is 40: 60.
Preferably, as a further practicable mode, in the mobile phase, the organic phase is methanol, the aqueous phase is a mixture of water, glacial acetic acid and triethylamine, and the volume ratio of the water, the glacial acetic acid and the triethylamine is (900-: (1-2): (1-2);
preferably, the volume ratio of the water, the glacial acetic acid and the triethylamine is 1000:1: 1.
Preferably, as a further implementable mode, the liquid chromatography employs a gradient elution procedure, the gradient elution procedure being:
the volume ratio of the organic phase to the aqueous phase is (40-41) within < 18 min: (59-60);
the volume ratio of the organic phase to the aqueous phase is (50-75) within 18 min: (25-50);
the volume ratio of the organic phase to the aqueous phase is (40-41) within more than 55 min: (59-60).
The high performance liquid chromatograph of the invention has no special requirements, and the chromatograph adopted by the invention is a Waters: 2695+2998 (PDA).
The above-mentioned specific separation and measurement method of the present invention can be realized in practice by the following method:
1) taking a proper amount of loxoprofen acid and salts thereof or preparation samples containing the loxoprofen acid and the salts thereof, dissolving the samples by using methanol, a mobile phase or diluent, and preparing a sample solution containing 0.1-3mg of loxoprofen acid per 1 mL.
2) Setting the flow rate of the mobile phase to be 0.5-2.0mL/min, preferably 1.0mL/min, the detection wavelength to be 200-250nm, the optimal detection wavelength to be 235nm, the temperature of the column incubator to be 20-50 ℃, and the optimal temperature of the column incubator to be 30 ℃.
3) Taking 10-50 mu L of the sample solution in the step 1), injecting the sample solution into a liquid chromatograph, and completing the separation and determination of the loxoprofen acid and the salt thereof and related substances, wherein: the type of the high performance liquid chromatograph has no special requirements, and the type of the adopted chromatograph is Waters: 2695+2998 (PDA).
One specific liquid chromatography procedure is given below:
sample preparation: dissolving loxoprofen acid and salt samples thereof by adopting a diluent, wherein the concentration is 2 mg/ml;
diluent agent: methanol: [ water: triethylamine: glacial acetic acid 1000:1:2 400: 600;
a chromatographic column: t3(
4.6×250mm，5μm)；
Flow rate: 1.0 ml/min;
detection wavelength: 235 nm;
column temperature: 30 ℃;
sample introduction amount: 20 mu l of the mixture;
mobile phase: water phase: water: triethylamine: glacial acetic acid (1000:1:1) organic phase: methanol, specific elution procedure is shown in table 1 below.
TABLE 1 gradient elution procedure
The method can effectively separate the loxoprofen acid and the related substances of the loxoprofen acid salt by adopting the T3 chromatographic column, solves the separation and measurement problems of the loxoprofen acid and the related substances, and ensures the controllable quality of the loxoprofen acid and the loxoprofen acid salt bulk drug.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method for separating and measuring the related substances contained in the loxoprofen acid and the loxoprofen salt can realize quantitative and qualitative measurement of the related substances contained in the loxoprofen acid and the loxoprofen salt, thereby effectively controlling the quality of the loxoprofen acid and the loxoprofen salt, more effectively realizing quality monitoring on the loxoprofen acid and the loxoprofen salt products, and having practical guiding significance for improving the quality of the related products;
(2) the method for separating and measuring related substances contained in the loxoprofen acid and the loxoprofen salt has the advantages of strong specificity, high accuracy and simple and convenient operation, is worthy of wide popularization and application, and can create wider economic benefits.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is an HPLC chart of loxoprofen sodium and related substances thereof in example 1 of the present invention;
FIG. 2 is an HPLC chart of loxoprofen sodium and related substances thereof in example 2 of the present invention;
FIGS. 3 to 5 are HPLC charts of loxoprofen sodium and related substances thereof in example 3 of the present invention;
FIG. 6 is an HPLC plot of a blank solvent of example 3 of the present invention;
FIG. 7 is an HPLC chart of loxoprofen sodium and related substances thereof in example 4 of the present invention;
FIG. 8 is an HPLC plot of a blank solvent of example 4 of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
The specific separation and measurement method comprises the following steps:
sample preparation: dissolving a loxoprofen acid and salt sample thereof by adopting a diluent, wherein the concentration is 2mg/ml, and injecting the loxoprofen acid and salt sample thereof into a liquid chromatograph;
diluent agent: methanol: [ water: triethylamine: glacial acetic acid 1000:1:1 ═ 40: 60;
a chromatographic column: t3(
4.6×250mm，5μm)；
Flow rate: 0.5 ml/min;
detection wavelength: 200 nm;
column temperature: 20 ℃;
sample introduction amount: 10 mu l of the mixture;
mobile phase: water phase: water: triethylamine: glacial acetic acid (900:1:1) organic phase: methanol, specific elution procedure is shown in table 2 below.
TABLE 2 gradient elution procedure
According to the invention, the loxoprofen acid and related substances of the loxoprofen acid salt can be effectively separated by adopting a T3 chromatographic column, high performance liquid chromatography analysis is carried out according to the conditions, a chromatogram is recorded, the result is shown in figure 1, the chromatographic peak with retention time of 41.081 in figure 1 is loxoprofen sodium, and the rest chromatographic peaks are impurity peaks of the loxoprofen sodium.
Example 2
The specific separation and measurement method comprises the following steps:
sample preparation: dissolving the loxoprofen acid and the salt sample thereof by adopting a diluent, wherein the concentration is 0.5mg/ml, and injecting the loxoprofen acid and the salt sample thereof into a liquid chromatograph;
diluent agent: methanol: [ water: triethylamine: glacial acetic acid 1100:1:2 ═ 50: 50;
a chromatographic column: t3(
4.6×250mm，5μm)；
Flow rate: 1.0 ml/min;
detection wavelength: 250 nm;
column temperature: 40 ℃;
sample introduction amount: 30 mu l of the mixture;
mobile phase: water phase: water: triethylamine: glacial acetic acid (1100:2:1) organic phase: methanol, specific elution procedure is shown in table 3 below.
TABLE 3 gradient elution procedure
According to the invention, the loxoprofen acid and related substances of the loxoprofen acid salt can be effectively separated by adopting a T3 chromatographic column, high performance liquid chromatography analysis is carried out according to the conditions, a chromatogram is recorded, the result is shown in figure 2, the chromatographic peak with retention time 34.146 in figure 2 is loxoprofen sodium, and the rest chromatographic peaks are impurity peaks of the loxoprofen sodium.
Example 3
The specific separation and measurement method comprises the following steps:
sample preparation: dissolving a loxoprofen acid and salt sample thereof by adopting a diluent, wherein the concentration is 3mg/ml, and injecting the loxoprofen acid and salt sample thereof into a liquid chromatograph;
diluent agent: methanol: [ water: triethylamine: glacial acetic acid 900:1:1 ═ 30: 70;
a chromatographic column: t3(
4.6×250mm，5μm)；
Flow rate: 2.0 ml/min;
detection wavelength: 235 nm;
column temperature: 25 ℃;
sample introduction amount: 20 mu l of the mixture;
mobile phase: water phase: water: triethylamine: glacial acetic acid (1000:1:2) organic phase: methanol, specific elution procedure is shown in table 4 below.
TABLE 4 gradient elution procedure
According to the invention, the loxoprofen acid and related substances of loxoprofen salts can be effectively separated by adopting a T3 chromatographic column, high performance liquid chromatography analysis is carried out according to the conditions, 3 samples record chromatograms, the results of the chromatograms are respectively shown in figures 3-5, the chromatographic peak with retention time of 35.055min in figure 3 is loxoprofen sodium, and the rest chromatographic peaks are impurity peaks of the loxoprofen sodium. In fig. 4, the peak of the chromatogram with the retention time of 35.052min is loxoprofen sodium, and it can be seen that loxoprofen sodium and impurities thereof can be completely separated under the condition, and the peak of the chromatogram with the retention time of 34.443min is loxoprofen sodium in fig. 5, and it can be seen that loxoprofen sodium and impurities thereof can be completely separated under the condition. Although the retention time of each sample may be somewhat different, the separation assay of the present invention can achieve complete separation, and FIG. 6 is a liquid chromatogram of a blank reagent in the absence of a sample, for comparison with the chromatograms of FIGS. 3-5 above.
Example 4
The specific separation and measurement method comprises the following steps:
sample preparation: dissolving a loxoprofen acid and salt sample thereof by adopting methanol, wherein the concentration is 1mg/ml, and injecting the loxoprofen acid and salt sample thereof into a liquid chromatograph;
a chromatographic column: thermo, BDS HYPERSIL C8, 4.6X 250mm, 5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 235 nm;
column temperature: 30 ℃;
sample introduction amount: 20 mu l of the mixture;
mobile phase: water phase: water: triethylamine: glacial acetic acid (1000:1:2) organic phase: methanol, specific elution procedure is shown in table 4 below.
TABLE 5 gradient elution procedure
According to the invention, the C8 chromatographic column is adopted, the loxoprofen acid and related substances of the loxoprofen acid and the loxoprofen salt can be effectively separated, the high performance liquid chromatography analysis is carried out according to the conditions, the chromatogram is recorded, the result is shown in the attached figures 7-8, the chromatographic peak with retention time of 25.158 in the figure 7 is loxoprofen sodium, the rest chromatographic peaks are loxoprofen sodium impurity peaks, and the figure 8 is a liquid chromatogram of a blank reagent when no sample is contained.
While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (13)
1. A method for separating and measuring related substances contained in loxoprofen acid and salts thereof, which is characterized by comprising the following steps:
injecting the loxoprofen acid and salt sample solution thereof into a liquid chromatograph for separation and detection;
wherein, the chromatographic column of the liquid chromatograph is a T3 column, the mobile phase is a mixture of an aqueous phase and an organic phase, and the ratio of the aqueous phase to the organic phase in the mobile phase is as follows: water: triethylamine: glacial acetic acid =900:1:1, organic phase methanol, gradient elution procedure:
or, the chromatographic column of the liquid chromatograph is a T3 column, the mobile phase is a mixture of an aqueous phase and an organic phase, and the ratio of the aqueous phase to the organic phase in the mobile phase is as follows: water: triethylamine: glacial acetic acid =1100:2:1, organic phase methanol, gradient elution procedure:
or, the chromatographic column of the liquid chromatograph is a T3 column, the mobile phase is a mixture of an aqueous phase and an organic phase, and the ratio of the aqueous phase to the organic phase in the mobile phase is as follows: water: triethylamine: glacial acetic acid =1000:1:2, organic phase methanol, gradient elution procedure:
or, the chromatographic column of the liquid chromatograph is a C8 column, the mobile phase is a mixture of an aqueous phase and an organic phase, and the ratio of the aqueous phase to the organic phase in the mobile phase is as follows: water: triethylamine: glacial acetic acid =1000:1:2, organic phase methanol, gradient elution procedure:
2. the separation and measurement method according to claim 1, wherein the solvent in the sample solution of loxoprofen acid or a salt thereof is methanol, a mobile phase or a diluent, and the diluent is a mixture of an aqueous phase and an organic phase.
3. The method for separation and measurement according to claim 1, wherein the loxoprofen acid and the salt thereof are one or a mixture of two of a loxoprofen metal salt and a loxoprofen acid ammonium salt.
4. The separation and assay method according to claim 1, wherein the concentration of loxoprofen acid or a salt thereof in the sample solution of loxoprofen acid or a salt thereof is 0.1 to 3 mg/ml.
5. The separation assay of claim 1, wherein the flow rate of the mobile phase is between 0.5 and 2.0 ml/min.
6. The separation assay of claim 1, wherein the flow rate of the mobile phase is 1.0 ml/min.
7. The separation and measurement method according to claim 1, wherein the detection wavelength of the liquid chromatograph is 200-250nm, and the column temperature is 20-40 ℃.
8. The separation and assay method according to claim 1, wherein the sample solution of loxoprofen acid or a salt thereof is injected in a volume of 10 to 30 μ L.
9. The separation and assay method according to claim 1, wherein the sample solution of loxoprofen acid or a salt thereof is injected in a volume of 20 μ L.
10. The separation and determination method according to claim 2, wherein in the diluent, the organic phase is methanol, the aqueous phase is a mixture of water, glacial acetic acid and triethylamine, and the volume ratio of the water, the glacial acetic acid and the triethylamine is (900-: (1-2): (1-2), the volume ratio of the organic phase to the aqueous phase is (30-50): (50-70).
11. The separation and measurement method according to claim 10, wherein the volume ratio of water, glacial acetic acid and triethylamine in the diluent is 1000:2: 1.
12. The separation assay of claim 10, wherein the volume ratio of organic phase to aqueous phase in the diluent is 40: 60.
13. The separation and measurement method according to claim 10, wherein the volume ratio of water, glacial acetic acid and triethylamine in the diluent is 1000:1: 1.
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| CN115236255B (en) * | 2022-08-04 | 2023-08-25 | 迪沙药业集团有限公司 | Method for detecting related substances of loxoprofen sodium |
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