CN110988163A - Method for separating and determining levocetirizine hydrochloride and genotoxic impurity E thereof by HPLC method - Google Patents
Method for separating and determining levocetirizine hydrochloride and genotoxic impurity E thereof by HPLC method Download PDFInfo
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Abstract
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining levocetirizine hydrochloride and genotoxic impurity E thereof by an HPLC method. The chromatographic column adopted in the method is characterized in that octadecyl bonded silica gel is used as a filler, a mixed mobile phase of potassium dihydrogen phosphate and methanol and/or acetonitrile is adopted for elution, and the eluted mobile phase enters a detector for detection. The method is a reversed-phase high-performance liquid chromatography, can simultaneously realize the separation and detection of levocetirizine hydrochloride and genotoxic impurity E thereof, has excellent separation performance and durability, is simple, convenient and feasible, has good reproducibility, is efficient and rapid, can achieve very good effect on both tailing factors and theoretical pedal number, can effectively determine the content of genotoxic impurity E in levocetirizine hydrochloride, and has strong specificity.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for separating and determining levocetirizine hydrochloride and genotoxic impurity E thereof by an HPLC method.
Background
Levocetirizine Hydrochloride (Levocetirizine Hydrochloride) is marketed in 2 months in 2001, is a third-generation antihistamine, is a single optical isomer (cetirizine TP-isomer) of the second-generation antihistamine, is developed by UCB company, is a selective histamine Hl receptor antagonist, has no obvious anticholinergic and anti-5-hydroxytryptamine effects, has small central inhibition effect, is mainly used for treating allergic diseases of respiratory systems, skins, eyes and the like, such as allergic rhinoconjunctivitis, allergic skin diseases, allergic asthma and the like, and has the advantages of quick response, strong and lasting effect and few side effects.
The levocetirizine hydrochloride is suitable for wide crowds, can be used for children, pregnant women and lactating women, and has the advantages of safety, reliability and obvious clinical effect. Levocetirizine hydrochloride has a chemical name of R-2- [2- [4- [ (4-chlorophenyl) phenylmethyl ] -1-piperazinyl ] ethoxy ] acetic acid, dihydrochloride, a molecular formula of C21H25ClN2O3 & 2HCl, and a structural formula shown as the following formula I:
the genotoxic impurity E has the chemical name of 2- (2-chloroethoxy) acetic acid and the structural formula II:
the content of genotoxic impurity E in levocetirizine hydrochloride is strictly controlled in the process of medicine synthesis and preparation. The analysis and separation of genotoxicity are always difficult and important points of quality control in the process of drug synthesis and preparation, and the separation of genotoxicity impurity E in levocetirizine hydrochloride has very important social significance and economic benefit in the aspect of quality control in the process of drug synthesis and preparation of levocetirizine hydrochloride.
The genotoxic impurity E generated in the process of preparing levocetirizine hydrochloride needs to be strictly controlled in both bulk drugs and preparations. At present, no relevant detection method is published.
Disclosure of Invention
In view of the above, an object of the present invention is to provide a method for separating genotoxic impurity E from levocetirizine hydrochloride raw material, which is simple to operate and has a high separation degree.
The structural formula of the levocetirizine hydrochloride is shown as a formula I:
the chemical name of the genotoxic impurity E is 2- (2-chloroethoxy) acetic acid, and the structural formula is shown as a formula II:
and separating genotoxic impurity E with high performance liquid chromatographic column filled with octadecyl bonded silica gel as fixed phase and mixed solution of potassium dihydrogen phosphate buffer salt, methanol and/or acetonitrile as mobile phase.
Further, the volume ratio of the monopotassium phosphate buffer salt to the methanol or/and the acetonitrile is 90-95:5-10, the concentration of the monopotassium phosphate buffer salt is 0.01-0.03 mol/L, and the pH value of the mobile phase is 2-4.
Further, there are many factors that affect the separation of drug impurities, and the composition of the mobile phase is a key factor that affects the separation for a given sample under a given stationary phase condition. The concentration of potassium dihydrogen phosphate is high, solid is easily precipitated when the potassium dihydrogen phosphate is mixed with methanol, and the concentration is low, so that the effect of ions on the reagent is not achieved, and the preferable concentration is 0.02 mol/L.
Further, the pH of the mobile phase system is 2-4. The pH and ionic strength of the mobile phase have great influence on the selectivity and the efficiency of the octadecyl bonded silica gel bonded phase, the salt is added into the mobile phase to form a buffer solution, the influence on the retention and the efficiency is larger than the influence on the selectivity, and the buffer and the analyte compete to occupy an octadecyl bonded silica gel cavity, so the retention of the solute is reduced and the efficiency is increased along with the increase of the strength of the buffer. The change in the pH of the mobile phase has a great influence on the dissociation of the solute, preferably pH 3.
Further, the flow rate of the mobile phase is 0.8-1.2 ml/min.
Furthermore, the separation time of genotoxic impurity E from levocetirizine hydrochloride is less than or equal to 60 minutes.
Further, the column selected was Waters XTerra, RP18, with a specification of 250X 4.6mm, 5 μm. The temperature of a chromatographic column box in the chromatographic analysis is 25-35 ℃. The binding constant of the solute to the octadecyl bonding silica gel is greatly influenced by temperature, the binding constant is increased at low temperature, but solute transfer is deteriorated, so that the selectivity of the octadecyl bonding silica gel bonding phase is increased by reducing the column temperature, and the separation degree is possibly reduced, but the separation of the strongly retained solute is improved by increasing the column temperature, so that the column box temperature of the chromatographic column is preferably 30 ℃ after experimental verification.
Further, the potassium dihydrogen phosphate buffer salt may be replaced with water or an acid or a base. Methanol and/or acetonitrile may be replaced by other organic solvents.
The second purpose of the invention is to provide a method for identifying levocetirizine hydrochloride and/or genotoxic impurity E. The method has the advantages of accurate identification and simple operation.
Setting the wavelength of a high performance liquid detector at 200-220nm, and separating levocetirizine hydrochloride and genotoxic impurity E by using the method of claim 1; when the retention time was 7.400. + -. 0.05 min, the sample was judged to contain the genotoxic impurity E. The detector wavelength is preferably 210 nm.
Further, when the retention time was 17.793 ± 0.05, it was judged that levocetirizine hydrochloride was contained.
The invention also aims to provide a method for detecting levocetirizine hydrochloride and/or genotoxic impurity E, wherein the levocetirizine hydrochloride genotoxic impurity E is a mixture. The method is simple to operate, and can effectively, accurately and efficiently detect the levocetirizine hydrochloride and/or the genotoxic impurity E.
The detection specifically comprises the following steps:
a separation
Separating genotoxic impurity E by using a high performance liquid chromatography column filled with octadecyl bonded silica gel as a stationary phase and a mixed solution of potassium dihydrogen phosphate buffer salt, methanol or/and acetonitrile as a mobile phase, wherein the genotoxic impurity E is 2- (2-chloroethoxy) acetic acid, and the structural formula is shown as the following formula II:
b detection
The wavelength of the high performance liquid detector is 200-220nm, if the peak is obtained when the retention time is 7.400 +/-0.05 minutes, the genotoxic impurity E is judged to be contained;
c calculated content
And calculating the peak area of the genotoxic impurity E, and calculating the content of the genotoxic impurity E by using an external standard method.
Further, in the step B, if the retention time is 17.793 ± 0.05, it is determined that levocetirizine hydrochloride is contained; in the step C, the peak area of the levocetirizine hydrochloride is calculated, and the content of the genotoxic impurity E is calculated by an external standard method.
Further, a formula for calculating the content of the genotoxic impurity E in the test solution is specifically as follows:
in the formula: cTIs the content of impurity E in the test solution,%;
CSthe concentration of the impurity E in the reference solution of the impurity E is g/ml;
ASthe peak response value of the impurity E in the reference solution of the impurity E is obtained;
ATthe peak response value is the impurity E peak response value in the test solution;
fuis the dilution factor of the test sample;
the above-mentioned
Further, a formula for calculating the content of the levocetirizine hydrochloride in the test solution is specifically as follows:
in the formula:
cr is the concentration of a reference solution of levocetirizine hydrochloride, mu g/ml;
ar is the average value of the main peak response values in the levocetirizine hydrochloride reference substance solution;
PScontent of reference substance,%;
CSthe concentration is the concentration of the test solution, mu g/ml;
as is the main peak response value in the test solution;
LOD is the loss on drying,%, of the test article.
Further, the preparation of the genotoxic impurity E reference substance and the test solution specifically comprises the following steps:
(1) preparing a gene virus impurity E solution: taking about 25mg of the impurity E reference substance, placing the reference substance in a 25ml measuring flask, adding a diluent to dissolve and dilute the reference substance to a scale, shaking up to obtain an impurity E solution,
(2) preparing a gene virus impurity E reference solution: precisely transferring 0.6ml of impurity E solution, placing in a 100ml measuring flask, adding diluent to dilute to scale, and shaking to obtain impurity E reference substance solution with concentration of 6 μ g/ml;
(3) preparing a test solution: weighing about 500mg of levocetirizine hydrochloride, placing the levocetirizine hydrochloride into a 25ml measuring flask, precisely transferring 2.5ml of impurity E storage solution, placing the impurity E storage solution into the same measuring flask, adding a diluent to dissolve and dilute the impurity E storage solution to a scale, and shaking up to obtain a test solution.
Further, the diluent is acetonitrile or an acetonitrile aqueous solution, and the volume ratio of acetonitrile to water in the acetonitrile aqueous solution is 5: 95.
Further, the basic research and S/N (signal to noise ratio) verification of the quantitative limit and the detection limit of the selected chromatographic system on the genotoxic impurity E are carried out.
Preparing a quantitative limiting solution: precisely weighing the impurity E reference substance, preparing a solution with a certain concentration, and diluting step by step to obtain a quantitative limit solution;
preparing a detection limiting solution: precisely transferring 7.0ml of the quantitative limiting solution, putting the quantitative limiting solution into a 20ml measuring flask, adding a diluent to dilute the quantitative limiting solution to a scale, and shaking up to obtain a detection limiting solution;
and taking the quantitative limit solution for continuous sample introduction for 3 times, taking the detection limit solution for continuous sample introduction for 2 times, and recording a chromatogram.
Further, it was verified whether the quantitative limit S/N (signal to noise ratio) of the impurity E and the detection limit S/N (signal to noise ratio) of 10:1 in the selected chromatographic system meet the requirements, based on the known and obtained data and by calculating the quantitative limit and the detection limit thereof according to the following formulas.
The invention has the beneficial effects that:
(1) the method for separating and detecting the levocetirizine hydrochloride and the genotoxic impurity E thereof can completely separate and detect the levocetirizine hydrochloride and the genotoxic impurity E thereof within 60 minutes, and has excellent separation performance and durability.
(2) The separation detection method provided by the invention takes octadecyl bonded silica gel as the filler, and the filler is durable, environment-friendly and low in toxicity and can quickly separate levocetirizine hydrochloride and genotoxic impurity E thereof.
(3) The method provided by the invention has the advantages of good separation degree, strong specificity and high sensitivity; and the operation is simple, convenient and quick.
Drawings
FIG. 1 is a high performance liquid chromatogram of an air-white solvent in example 1.
FIG. 2 is a high performance liquid chromatogram of the test solution of example 2.
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.
In the following examples and comparative examples, the apparatus and chromatographic conditions used were as follows:
high performance liquid chromatograph: shimadzu LC-20AT
A chromatographic column: waters XTerra, RP18 (250X 4.6mm, 5 μm)
The detector detects the wavelength: 210nm
Flow rate of mobile phase: 1.0ml/min
Column temperature of chromatographic column box: 30 deg.C
Sample introduction amount: 20 μ l
Diluent (solvent for dissolving control and test sample): 5% acetonitrile (acetonitrile V: water V ═ 95: 5).
Example 1
Mobile phase A: weighing 2.72 parts of monopotassium phosphate (0.02mol/L monopotassium phosphate) in a 1000ml volumetric flask, adding water to dissolve and dilute the monopotassium phosphate to a scale, and adjusting the pH value to 3.0 +/-0.1 by using phosphoric acid;
mobile phase B: acetonitrile;
the volume ratio of mobile phase a to mobile phase B was 95: 5.
(1) preparation of the solution
Preparing an impurity E solution: and taking about 25mg of the impurity E reference substance, placing the reference substance in a 25ml measuring flask, adding a diluent to dissolve and dilute the reference substance to a scale, and shaking up to obtain the impurity E storage solution.
Preparing an impurity E reference substance solution: precisely transferring 0.6ml of the solution, placing the solution into a 100ml measuring flask, adding a diluent to dilute the solution to a scale, and shaking up to obtain a reference substance solution with the impurity E concentration of 6 mu g/ml.
Preparing a levocetirizine hydrochloride test solution: weighing about 500mg of levocetirizine hydrochloride, placing the levocetirizine hydrochloride into a 25ml measuring flask, precisely transferring 2.5ml of impurity E storage solution, placing the levocetirizine hydrochloride into the same measuring flask, adding a diluent to dissolve and dilute the levocetirizine hydrochloride to a scale, and shaking up to obtain a test solution, wherein the content of the levocetirizine hydrochloride in the obtained test solution is 15-25 mg/ml.
(2) Sample introduction detection
And (3) respectively sampling the diluent and the test solution in the step (1) according to the chromatographic conditions, recording a chromatogram, and obtaining a measurement result shown in table 1. The chromatogram is shown in FIG. 1 and FIG. 2.
TABLE 1 test results
And (4) conclusion: blank diluent does not interfere with sample determination; the separation degree between the impurity E and the levocetirizine hydrochloride peak is more than 1.5; the tests prove that the levocetirizine hydrochloride has good separation from the impurity E peak and strong specificity.
Example 2 comparative example 1
Mobile phase A: and (3) water.
Mobile phase B: acetonitrile;
the volume ratio of mobile phase a to mobile phase B was 95: 5.
sample introduction is carried out on the sample solution prepared in the step 1) of the example 1 according to the chromatographic conditions, a chromatogram is recorded, and the measurement result is shown in a table 2.
TABLE 2 test results
And (4) conclusion: unlike the mobile phase A in example 1, the separation degree of the impurity E and the levocetirizine hydrochloride peak is 9.00, but the impurity E has poor and not sharp peak shape, and the peak emergence time is relatively late, so that the sensitivity cannot meet the requirement. The addition of salts into the mobile phase can advance the peak-producing time and has a better peak pattern.
Example 3 comparative example 2
Mobile phase A: weighing 0.92g (0.02 mol/L) of formic acid into a 1000ml volumetric flask, adding water to dissolve and dilute the formic acid to a scale, and adjusting the pH value to 3.0 +/-0.1 by using phosphoric acid;
mobile phase B: acetonitrile;
the volume ratio of mobile phase a to mobile phase B was 95: 5.
the sample solution prepared in step (1) of example 1 was sampled under the above-mentioned chromatographic conditions, and the chromatogram was recorded, and the measurement results are shown in Table 3.
TABLE 3 test results
And (4) conclusion: in the separation test which is the same as other conditions of the above example and is only different from the mobile phase A, the impurity E has a peak, and the levocetirizine hydrochloride does not have a peak, but the impurity E has a poor peak shape and is not sharp, and the sensitivity cannot meet the requirement. The effect of adding salts as buffer salts into the mobile phase is better than that of adding acids as buffer salts into the mobile phase.
Example 4 basic research of detection limit and quantification limit of genotoxic impurity E by chromatographic system
(1) Solution preparation
Preparing a quantitative limiting solution: and precisely weighing the impurity E photo, preparing a solution with a certain concentration, and diluting step by step to obtain a quantitative limit solution.
Preparing a detection limiting solution: precisely transferring 7.0ml of the quantitative limiting solution, putting the quantitative limiting solution into a 20ml measuring flask, adding a diluent to dilute the quantitative limiting solution to a scale, and shaking up to obtain the detection limiting solution.
(2) Sample introduction determination and calculation of quantitative limit and detection limit
And taking the quantitative limit solution for continuous sample introduction for 3 times, taking the detection limit solution for continuous sample introduction for 2 times, recording a chromatogram, 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.
TABLE 4 quantitative Limit determination results
TABLE 5 measurement results of detection limits
And (4) conclusion: from the above experimental data, the quantitative limit S/N (signal-to-noise ratio) 3 of the impurity E in the chromatographic system is as follows: 1 and the detection limit S/N (signal to noise ratio) meet the 10:1 requirement.
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)
1. A method for separating genotoxic impurity E from levocetirizine hydrochloride raw material is characterized in that a high performance liquid chromatography column filled with octadecyl bonded silica gel is used as a stationary phase, a mixed solution of monopotassium phosphate buffer salt, methanol or/and acetonitrile is used as a mobile phase to separate genotoxic impurity E, the genotoxic impurity E is 2- (2-chloroethoxy) acetic acid, and the structural formula of the genotoxic impurity E is as the following formula II:
2. the method according to claim 1, wherein the volume ratio of the potassium dihydrogen phosphate buffer salt to the methanol or/and acetonitrile is 90-95:5-10, the concentration of the potassium dihydrogen phosphate buffer salt is 0.01mol/L-0.03mol/L, and the pH value of the mobile phase is 2-4.
3. The method of claim 1, wherein the flow rate of the mobile phase is 0.8-1.2 ml/min.
4. The method of claim 1, wherein the separation time is 60 minutes or less.
5. The method for identifying levocetirizine hydrochloride and/or genotoxic impurity E is characterized in that the wavelength of a high performance liquid detector is 200-220nm, and the levocetirizine hydrochloride and the genotoxic impurity E are separated by the method of claim 1; when the retention time was 7.400. + -. 0.05 min, the sample was judged to contain the genotoxic impurity E.
6. The method of claim 5, wherein levocetirizine hydrochloride is determined to be contained if the retention time is 17.793 ± 0.05 peaks.
7. The method for detecting levocetirizine hydrochloride and/or genotoxic impurity E is characterized by comprising the following steps:
a separation
Separating genotoxic impurity E by using a high performance liquid chromatography column filled with octadecyl bonded silica gel as a stationary phase and a mixed solution of potassium dihydrogen phosphate buffer salt, methanol or/and acetonitrile as a mobile phase, wherein the genotoxic impurity E is 2- (2-chloroethoxy) acetic acid, and the structural formula is shown as the following formula II:
b detection
The wavelength of the high performance liquid detector is 200-220nm, if the peak is obtained when the retention time is 7.400 +/-0.05 minutes, the genotoxic impurity E is judged to be contained;
c calculated content
And calculating the peak area of the genotoxic impurity E, and calculating the content of the genotoxic impurity E by using an external standard method.
8. The method according to claim 7, wherein in step B, if the retention time is 17.793 ± 0.05, it is determined that levocetirizine hydrochloride is contained; in the step C, the peak area of the levocetirizine hydrochloride is calculated, and the content of the levocetirizine hydrochloride is calculated by an external standard method.
9. The method of claim 7, wherein the amount of genotoxic impurity E is calculated by the formula:
in the formula: cTIs the content of impurity E in the test solution,%;
CSthe concentration of the impurity E in the reference solution of the impurity E is g/ml;
ASthe peak response value of the impurity E in the reference solution of the impurity E is obtained;
ATthe peak response value is the impurity E peak response value in the test solution;
fuis the dilution factor of the test sample;
the above-mentioned
10. The method of claim 8, wherein the levocetirizine hydrochloride content is calculated by the formula:
in the formula:
cr is the concentration of a reference solution of levocetirizine hydrochloride, mu g/ml;
ar is the average value of the main peak response values in the levocetirizine hydrochloride reference substance solution;
PScontent of reference substance,%;
CSthe concentration is the concentration of the test solution, mu g/ml;
ASthe main peak response value in the test solution is obtained;
LOD is the loss on drying,%, of the test article.
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| CN115047122A (en) * | 2022-06-29 | 2022-09-13 | 重庆华邦胜凯制药有限公司 | Analysis method of impurities generated in rifapentine and synthesis process thereof |
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| 董芮娟 等: "HPLC法测定盐酸左西替利嗪有关物质", 《浙江海洋学院学报(自然科学版)》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115047122A (en) * | 2022-06-29 | 2022-09-13 | 重庆华邦胜凯制药有限公司 | Analysis method of impurities generated in rifapentine and synthesis process thereof |
| CN115047122B (en) * | 2022-06-29 | 2023-05-02 | 重庆华邦胜凯制药有限公司 | Method for analyzing impurities generated in rifapentine and synthesis process thereof |
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