CN111505150A - Method for detecting potential mutation-causing impurities in pitavastatin calcium tablets - Google Patents
Method for detecting potential mutation-causing impurities in pitavastatin calcium tablets Download PDFInfo
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- CN111505150A CN111505150A CN202010363066.2A CN202010363066A CN111505150A CN 111505150 A CN111505150 A CN 111505150A CN 202010363066 A CN202010363066 A CN 202010363066A CN 111505150 A CN111505150 A CN 111505150A
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/86—Signal analysis
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/047—Standards external
Abstract
The invention relates to the field of medicine quality detection, in particular to a method for detecting potential mutation-causing impurities in pitavastatin calcium tablets, which is characterized in that a sample to be detected is dissolved by a solvent and then is detected by a high performance liquid chromatography, wherein the chromatographic conditions comprise that a mobile phase comprises an organic acid salt buffer solution and acetonitrile, the flow rate is 1.0m L/min, the column temperature is 25-40 ℃, a chromatographic column comprises octadecylsilane bonded silica gel as a filling agent, the sample injection volume is 50 mu L, the detection wavelength is 270-280 nm, the elution mode comprises gradient elution, and the potential mutation-causing impurities comprise impurity 1 and impurity 2.
Description
Technical Field
The invention relates to the field of medicine quality detection, in particular to a method for detecting potential mutation-causing impurities in pitavastatin calcium tablets.
Background
Statins are widely used for reducing blood fat, cholesterol and the like as HMG-CoA reductase inhibitors, pitavastatin is known as super statin, pitavastatin calcium tablets are the current international latest generation of hypercholesterolemia treatment medicaments, and compared with similar products, the pitavastatin calcium tablets have the advantages of small dosage, less side effect, exact curative effect and the like. It is reported that pitavastatin calcium has the effect of remarkably reducing low-density lipoprotein cholesterol, the effect is stronger than that of other statins, and the medicine is effective to juvenile patients and has wide clinical value.
Pitavastatin calcium is easily degraded after being irradiated by light to generate a plurality of impurities, wherein the impurities comprise a plurality of potential mutation-causing impurities with warning structures, and the impurity 1 and the impurity 2 (the specific structures are shown in table 1) are two of the impurities. The medicine containing the impurities easily affects the quality and safety of the medicine, possibly causes adverse reactions, and needs to be researched and controlled according to the requirements of relevant guidelines.
TABLE 1 Structure and chemical name of impurity 1 and impurity 2
At present, in the domestic and foreign pharmacopoeias, except the japanese pharmacopoeia which contains pitavastatin calcium tablets, other pharmacopoeias do not contain pitavastatin calcium tablets. Through tests, the method for detecting the related substances carried by the JP17 pitavastatin calcium tablet can separate and detect various impurities, but cannot detect the contents of the impurity 1 and the impurity 2, and the characteristic peaks of the impurity 1 and the impurity 2 cannot be separated from other impurity peaks in the detection process, so that the detection of the impurity 1 and the impurity 2 is interfered.
Disclosure of Invention
In view of the above disadvantages, the present invention aims to provide a method for detecting a potential mutation-causing impurity in a pitavastatin calcium tablet, which can realize effective separation of pitavastatin calcium, the impurity 1 and the impurity 2, accurately detect the content of the potential mutation-causing impurity 1 and the impurity 2 in the pitavastatin calcium tablet, has characteristics of simple operation, easy control, high sensitivity, good specificity, good system applicability, good solution stability and good chromatographic condition durability, provides an effective detection method for monitoring product quality, and further ensures product safety.
The method for detecting the potential mutagenic impurities in the pitavastatin calcium tablet disclosed by the invention is characterized in that a sample to be detected is dissolved by a solvent and then is detected by a high performance liquid chromatography, wherein the chromatographic conditions are as follows:
mobile phase: organic acid salt buffer solution and acetonitrile;
the flow rate is 1.0m L/min;
column temperature: 25-40 ℃, preferably 30 ℃;
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent;
the sample injection volume is 50 mu L;
detection wavelength: 270-280 nm, preferably 275 nm;
and (3) an elution mode: gradient elution;
wherein, the potential mutation-causing impurities are impurity 1 and impurity 2, and the structure of impurity 1Comprises the following steps:
the structure of impurity 2 is:
wherein:
the method adopts high performance liquid chromatography for detection, adopts a reversed phase high performance liquid chromatography system, and has the following gradient elution procedures:
| time (min) | Organic acid salt buffer (%) | Acetonitrile (%) |
| 0 | 60 | 40 |
| 5 | 60 | 40 |
| 40 | 35 | 65 |
| 42 | 10 | 90 |
| 50 | 10 | 90 |
| 51 | 60 | 40 |
The organic acid salt buffer solution is an acetate buffer solution, and the pH value is 3.4-3.6.
The solvent is acetonitrile-water solution, and the volume content of acetonitrile is 40-60%.
The method for detecting the potential mutagenic impurities in the pitavastatin calcium tablets specifically comprises the following steps:
(1) preparing a sample solution;
(2) preparing a system applicability solution;
(3) preparing an impurity reference substance solution;
(4) the detection method comprises the following steps: high performance liquid chromatography is adopted, a gradient elution program is utilized for impurity separation, and the content of impurities is controlled by a limit method.
Wherein, the preferred technical scheme is as follows:
in the step (1), the preparation method of the sample solution comprises the steps of taking a sample which is equivalent to 20mg of pitavastatin calcium, adding a solvent, carrying out ultrasonic dissolution, diluting to a constant volume of 40m L, centrifuging or standing, and taking supernate to obtain the sample solution.
In the step (2), the preparation method of the system applicability solution comprises the steps of weighing a pitavastatin calcium reference substance, a pitavastatin calcium impurity 1 reference substance and a pitavastatin calcium impurity 2 reference substance, dissolving and diluting with a solvent to prepare a mixed solution containing 0.5mg/m L of pitavastatin calcium, 10.15 mu g/m L of impurities and 20.15 mu g/m L of impurities, and obtaining the system applicability solution.
In the step (3), the impurity reference substance solution is prepared by weighing pitavastatin calcium impurity 1 reference substance and impurity 2 reference substance, dissolving and diluting with a solvent to prepare a mixed solution containing 10.15 μ g/m L of impurity and 20.15 μ g/m L of impurity, thus obtaining the impurity reference substance solution.
Compared with the prior art, the invention has the following beneficial effects:
1. the method can realize the effective separation of pitavastatin calcium, the impurity 1 and the impurity 2; meanwhile, the interference of other related impurities of the pitavastatin calcium on the detection of the impurity 1 and the impurity 2 is avoided, the content of the potential mutation-causing impurity 1 and the impurity 2 of the pitavastatin calcium tablet can be accurately detected, the quality of the pitavastatin calcium tablet is effectively monitored, and the medication safety is improved.
2. The detection method for the potential mutagenic impurities in the pitavastatin calcium tablet is simple to operate, easy to control and high in sensitivity, has good specificity, system applicability, solution stability and chromatographic condition durability, provides an effective detection method for monitoring the product quality, and further guarantees the product safety.
Drawings
FIG. 1 is a chromatogram of a system suitability solution;
FIG. 2 is a chromatogram of pitavastatin calcium tablet blank auxiliary material;
FIG. 3 is a chromatogram of a test solution of pitavastatin calcium tablet;
figure 4 is a chromatogram of an impurity control solution.
Detailed Description
In order to make the purpose, technical solution and effect of the present application clearer and clearer, the present invention is further described below with reference to the following embodiments. Are provided for illustration only and are not intended to limit the scope of the present invention.
The impurity 1 and the impurity 2 can be generated by pitavastatin calcium degradation through illumination, and the structures of the two impurities contain warning structure fragments of polycyclic aromatic hydrocarbon, and the warning structure fragments are researched and controlled according to the requirements of relevant guidelines such as ICHM 7 and the like.
The high performance liquid chromatography used in the following examples, which is not specifically described, was carried out under the conditions of a column using octadecylsilane chemically bonded silica as a filler, a specification of 250 × 4.6.6 mm, 5 μm, Shimadzu ODS-3 series, a column temperature of 30 ℃, a flow rate of 1.0m L/min, a UV detector having a detection wavelength of 275nm, and a sample injection volume of 50 μ L.
Wherein the mobile phase of the high performance liquid chromatography comprises: mobile phase A, 0.01M acetate buffer, pH 3.5; mobile phase B, acetonitrile; gradient elution was performed using the following procedure:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 60 | 40 |
| 5 | 60 | 40 |
| 40 | 35 | 65 |
| 42 | 10 | 90 |
| 50 | 10 | 90 |
| 51 | 60 | 40 |
The mobile phase A was prepared by weighing 0.6g of acetic acid, diluting to 1L with deionized water, and adjusting the pH to 3.5 with sodium acetate solution.
Experiments prove that the organic filter membrane has an adsorption effect on the impurities 2, which can reduce the chromatographic peak area, so that the sample is preferably treated by centrifugation or standing, and the filter membrane cannot be used for filtration.
The preparation of the impurity reference solution comprises weighing 5.0mg of each of impurity 1 and impurity 2, placing in a 100m L measuring flask, adding solvent to dissolve and dilute to scale, shaking up to obtain impurity reference mother liquor, placing 3m L of impurity reference mother liquor in a 100m L measuring flask, diluting with solvent to scale, shaking up to obtain impurity reference stock solution, placing 2m L of impurity reference stock solution in a 20m L measuring flask, diluting with solvent to scale, and shaking up to obtain impurity reference stock solution.
The preparation of the sample solution comprises taking 20 1mg pitavastatin calcium tablets, placing into a 40m L measuring flask, adding solvent to 2/3 of the volume of the measuring flask, performing ultrasonic treatment for 10min, taking out, diluting with solvent to scale, shaking up, centrifuging, and taking supernatant as the sample solution.
The preparation method of the system applicability solution comprises weighing 20.0mg of pitavastatin calcium reference substance, placing in a 40m L measuring flask, adding appropriate amount of solvent, performing ultrasonic treatment to dissolve, adding 4m L of impurity reference substance stock solution, diluting with solvent to scale, and shaking.
Preparing mixed sample solution by taking 20 1mg pitavastatin calcium tablets, placing into a 40m L measuring flask, adding a solvent to 2/3 of the volume of the measuring flask, performing ultrasonic treatment for 10min, taking out, adding an impurity reference substance stock solution of 4m L, diluting to scale with the solvent, shaking up, centrifuging, and taking supernatant to obtain the pitavastatin calcium tablet.
Example 1
Good specificity:
the verification proves that (1) the solvent and the blank auxiliary materials do not interfere the detection of the main peak of pitavastatin calcium, the peak of impurity 1 and the peak of impurity 2; (2) the separation degree between the main peak and the adjacent impurities and between the adjacent impurities is not less than 1.5; (3) system applicability the retention time and degree of separation of each peak in the solution are shown in table 2.
TABLE 2 System applicability solution test results
Example 2
Good system applicability:
the solvent does not interfere the detection of each peak, and the number of theoretical plates of the main peak is 15977; impurity 1 theoretical plate number 45800, tailing factor 1.19; impurity 2 theoretical plate number 116945, tailing factor 1.05; and continuously feeding the impurity reference substance solution for 5 times, wherein the RSD of the peak areas of the impurity 1 and the impurity 2 is less than 1 percent. The results showed good systematicness.
Example 3
Good sensitivity:
the detection limit of the impurities is examined. And taking a proper amount of reference substance solutions of the impurities 1 and 2, and gradually diluting the reference substance solutions by using a solvent, wherein the sample concentration corresponding to the signal-to-noise ratio of about 3:1 or 2:1 is the detection limit. The test results are shown in table 3.
TABLE 3 detection limit results for impurity 1 and impurity 2
| Impurities | Concentration (μ g/m L) | Peak area | S/ |
| Impurity | |||
| 1 | 0.0068 | 1683 | 3.34 |
| Impurity 2 | 0.0026 | 813 | 3.15 |
Example 4
Good stability:
through testing, the adopted sample does not contain impurities 1 and 2, and in order to better examine the stability of the sample, the mixed sample solution added with the impurity reference substance is used for replacing the sample solution for testing. And taking the impurity reference substance solution and the mixed sample solution, and respectively carrying out sample injection detection at different times, wherein the test results are shown in tables 4 and 5. RSD of peak areas of the chromatographic peaks of the impurity reference substance solution and the mixed sample solution is less than 5% within 36 hours, and stability is good.
TABLE 4 stability test results of mixed sample solutions
TABLE 5 stability test results for impurity control solutions
Example 5
Good durability:
the test is carried out on the temperature +/-5 ℃, the flow rate +/-0.2 m L/min, the pH +/-0.1 of a mobile phase and different chromatographic columns, the system applicability solution, the impurity reference substance solution and the mixed sample solution are respectively taken to be tested under various conditions, the content of impurities is statistically analyzed, and the test results are shown in tables 6 and 7.
Table 6 impurity 1 durability test results
Table 7 impurity 2 durability test results
According to the test results of the above examples, the detection method of potential mutation-causing impurities in pitavastatin calcium tablets has the advantages of simple operation, easy control, high sensitivity, good specificity, system applicability, solution stability and chromatographic condition durability, provides an effective detection method for monitoring the product quality, and further ensures the product safety.
Claims (10)
1. A method for detecting potential mutagenic impurities in pitavastatin calcium tablets is characterized by comprising the following steps: dissolving a sample to be detected by adopting a solvent, and detecting by adopting a high performance liquid chromatography, wherein the chromatographic conditions are as follows:
mobile phase: organic acid salt buffer solution and acetonitrile;
the flow rate is 1.0m L/min;
column temperature: 25-40 ℃;
a chromatographic column: octadecylsilane chemically bonded silica is used as a filling agent;
the sample injection volume is 50 mu L;
detection wavelength: 270-280 nm;
and (3) an elution mode: gradient elution;
wherein, the potential mutation-causing impurities are impurity 1 and impurity 2, and the structure of the impurity 1 is as follows:
the structure of impurity 2 is:
2. the method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the method adopts high performance liquid chromatography for detection, adopts a reversed phase high performance liquid chromatography system, and has the following gradient elution procedures:
3. the method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the organic acid salt buffer solution is an acetate buffer solution, and the pH value is 3.4-3.6.
4. The method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the solvent is acetonitrile-water solution, and the volume content of acetonitrile is 40-60%.
5. The method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the column temperature was 30 ℃.
6. The method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the detection wavelength is 275 nm.
7. The method for detecting potential mutagenic impurities in pitavastatin calcium tablet as claimed in claim 1, wherein: the method comprises the following steps:
(1) preparing a sample solution;
(2) preparing a system applicability solution;
(3) preparing an impurity reference substance solution;
(4) the detection method comprises the following steps: high performance liquid chromatography is adopted, a gradient elution program is utilized for impurity separation, and the content of impurities is controlled by a limit method.
8. The method for detecting the potential mutation-causing impurities in the pitavastatin calcium tablet as claimed in claim 7, wherein the sample solution is prepared by the steps of (1) adding a solvent to a sample containing 20mg of pitavastatin calcium, dissolving the sample by ultrasound, diluting to a constant volume of 40m L, centrifuging or standing, and collecting the supernatant to obtain the sample solution.
9. The method for detecting potential mutation-causing impurities in pitavastatin calcium tablets as claimed in claim 7, wherein the method for preparing the system suitability solution in the step (2) comprises weighing a pitavastatin calcium reference substance, a pitavastatin calcium impurity 1 reference substance and a pitavastatin calcium impurity 2 reference substance, dissolving and diluting the pitavastatin calcium reference substance with the solvent to prepare a mixed solution containing 0.5mg/m L of pitavastatin calcium, 10.15 μ g/m L of impurities and 20.15 μ g/m L of impurities, thereby obtaining the system suitability solution.
10. The method for detecting potential mutation-causing impurities in pitavastatin calcium tablets as claimed in claim 7, wherein the impurity reference substance solution in the step (3) is prepared by weighing a pitavastatin calcium impurity 1 reference substance and an impurity 2 reference substance, dissolving and diluting with a solvent to prepare a mixed solution containing 10.15 μ g/m L of impurities and 20.15 μ g/m L of impurities, thereby obtaining the impurity reference substance solution.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010363066.2A CN111505150A (en) | 2020-04-30 | 2020-04-30 | Method for detecting potential mutation-causing impurities in pitavastatin calcium tablets |
| PCT/CN2020/101228 WO2021217887A1 (en) | 2020-04-30 | 2020-07-10 | Testing method for potential mutagenic impurities in pitavastatin calcium tablet |
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| CN202010363066.2A CN111505150A (en) | 2020-04-30 | 2020-04-30 | Method for detecting potential mutation-causing impurities in pitavastatin calcium tablets |
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| CN114076802A (en) * | 2020-08-21 | 2022-02-22 | 徐州万邦金桥制药有限公司 | Analysis method for quantitatively detecting nitrogen and oxygen impurities in pitavastatin calcium |
| CN114295748A (en) * | 2021-12-30 | 2022-04-08 | 苏州正济药业有限公司 | Detection method for pitavastatin calcium intermediate and impurities |
| CN114295746A (en) * | 2021-12-27 | 2022-04-08 | 卓和药业集团股份有限公司 | Analysis and detection method of pitavastatin calcium |
| CN114384178A (en) * | 2021-12-30 | 2022-04-22 | 苏州正济医药研究有限公司 | Detection method for pitavastatin calcium intermediate and impurities |
| CN115166104A (en) * | 2022-09-08 | 2022-10-11 | 康瑞鑫(天津)药物研究院有限公司 | Method for separating pitavastatin calcium starting material and impurities thereof and application |
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| CN100371709C (en) * | 2005-12-12 | 2008-02-27 | 重庆医药工业研究院有限责任公司 | Method for separating and determining pitavastatin and its optical isomer by means of liquid chromatography |
| CN102285917B (en) * | 2011-09-20 | 2013-12-11 | 海南美大制药有限公司 | Pitavastatin calcium compound and preparation method thereof |
| CN109254106A (en) * | 2018-10-16 | 2019-01-22 | 迪沙药业集团（天津）药物研究有限公司 | A kind of method of quality control of Pitavastatin Calcium side chain |
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2020
- 2020-04-30 CN CN202010363066.2A patent/CN111505150A/en not_active Withdrawn
- 2020-07-10 WO PCT/CN2020/101228 patent/WO2021217887A1/en active Application Filing
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| CN114076802A (en) * | 2020-08-21 | 2022-02-22 | 徐州万邦金桥制药有限公司 | Analysis method for quantitatively detecting nitrogen and oxygen impurities in pitavastatin calcium |
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| CN114384178A (en) * | 2021-12-30 | 2022-04-22 | 苏州正济医药研究有限公司 | Detection method for pitavastatin calcium intermediate and impurities |
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| CN114295748B (en) * | 2021-12-30 | 2023-11-10 | 苏州正济药业有限公司 | Method for detecting pitavastatin calcium intermediate and impurities |
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| CN115166104A (en) * | 2022-09-08 | 2022-10-11 | 康瑞鑫(天津)药物研究院有限公司 | Method for separating pitavastatin calcium starting material and impurities thereof and application |
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