CN112557558B - Method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets - Google Patents
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Abstract
The invention discloses a method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets, which belongs to the technical field of chemical substance detection, wherein the specification of the ezetimibe simvastatin tablets is that each ezetimibe tablet contains 10mg of ezetimibe and 80mg of simvastatin, and the detection method adopts a high performance liquid chromatography to detect SCH59566 impurity content. The method for detecting the SCH59566 impurity content has strong specificity, the SCH59566 impurity peak can be separated from the baseline of other impurity peaks, the peak type is better, and the impurity content is more accurately calculated.
Description
Technical Field
The invention relates to impurity content detection, in particular to SCH59566 impurity content detection in ezetimibe simvastatin tablets, and belongs to the technical field of chemical substance detection.
Background
Ezetimibe simvastatin tablets are the only global lipid-lowering compound preparation at present, combine two lipid-lowering drugs, simvastatin and Ezetimibe, which are widely applied clinically, and are suitable for patients with hypercholesterolemia. The ezetimibe simvastatin tablet has double mechanisms, inhibits the synthesis of cholesterol in the liver and inhibits the absorption of the cholesterol in the small intestine, thereby providing a strong and safe treatment scheme and helping a patient break through the bottleneck of reaching the LDL-C standard. 2015, the Chinese expert consensus on the clinical application of selective cholesterol absorption inhibitor mentions that the ezetimibe and simvastatin which are jointly applied have good safety and tolerance, and that patients with homozygous familial hypercholesterolemia who have failed to reach the blood lipid standard after receiving special treatment (such as plasma replacement therapy) are treated. Clinical research shows that the ezetimibe simvastatin tablet can reduce the low-density lipoprotein cholesterol (LDL-C) of a patient by more than 50% by starting treatment, and the risk of cardiovascular diseases is fundamentally reduced. Meanwhile, the single dosage is small, so the probability of adverse reaction is greatly reduced, and the tolerance is good.
SCH59566, an ezetimibe tetrahydropyran impurity derived from ezetimibe degradation impurities, chemical name: (2R,3R,6S) -N,6-bis (4-fluorophenyl) -2- (4-hydroxyphenyl) tetrahydro-2H-pyran-3-carboxamide, CAS number: 1296129-15-1, formula: c24H21F2NO3Molecular weight: 409.4252464, boiling point: 626.7 ± 55.0 ℃, density: 1.315 ± 0.06g/cm3, acidity index (pKa): 9.89 ± 0.30, english name: EzetiMibe tetrahedron inpurity, chemical name in english: (2R,3R,6S) -N,6-Bis (4-fluorophenyl) tetrahydro-2- (4-hydroxyphenyl) -2H-pyran-3-carboxaMide, having the structural formula:
the content of SCH59566 impurity in ezetimibe simvastatin tablets can reduce the effective content of ezetimibe, interfere the function of ezetimibe and simvastatin tablets and increase the probability of side effect. Therefore, the control of the content of the SCH59566 impurity has important significance for improving the quality of the ezetimibe simvastatin tablets. No method for detecting the content of SCH59566 impurity in ezetimibe simvastatin tablets exists in the prior art. In the prior art, chromatography is usually adopted to detect the content of related substances in ezetimibe, but the detection method is not suitable for detecting the content of SCH59566 impurity in ezetimibe simvastatin tablets, and SCH59566 impurity and linked impurity in ezetimibe simvastatin tablets can not be effectively separated. In addition, the ezetimibe simvastatin tablets have multiple specifications, one specification is that each ezetimibe simvastatin tablet contains 10mg of ezetimibe and 20mg of simvastatin, the other specification is that each ezetimibe simvastatin tablet contains 10mg of ezetimibe and 80mg of simvastatin, and related impurity types and contents in the ezetimibe simvastatin tablets with different specifications have certain difference and influence on detection of SCH59566 impurity content to different degrees.
Disclosure of Invention
The invention aims to provide a method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets, and accurately detect SCH59566 impurity content.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets is characterized in that each ezetimibe simvastatin tablet contains 10mg of ezetimibe and 80mg of simvastatin, and high performance liquid chromatography is adopted to detect SCH59566 impurity content.
The technical scheme of the invention is further improved as follows: the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecylsilane chemically bonded silica;
mobile phase: the mobile phase A is a mixed solution of 0.1% phosphoric acid water solution, acetonitrile, methanol and tetrahydrofuran, and the mobile phase B is acetonitrile;
and (3) an elution mode: gradient elution;
detection wavelength: 231 nm;
flow rate: 1.0 ml/min;
column temperature: 45 ℃;
sample loading amount: 10 μ l.
The technical scheme of the invention is further improved as follows: the column was model Waters XTerra RP18 (250X 4.6mm,5 μm).
The technical scheme of the invention is further improved as follows: the volume ratio of the 0.1% phosphoric acid aqueous solution, the acetonitrile, the methanol and the tetrahydrofuran in the mobile phase A is 55:35:9: 1.
The technical scheme of the invention is further improved as follows: the gradient elution is specifically that the volume of the mobile phase A accounts for 95% and the volume of the mobile phase B accounts for 5% within 0-25 min, the volume of the mobile phase A accounts for 0 and the volume of the mobile phase B accounts for 100% within 25-35 min, and the volume of the mobile phase A accounts for 95% and the volume of the mobile phase B accounts for 5% within 35-45 min.
The technical scheme of the invention is further improved as follows: the detection method comprises the following steps:
s1 preparing a reference solution and a test solution;
s2 precisely measuring 10 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram;
s3, calculating the peak consistent with the SCH59566 retention time in the chromatogram of the test solution according to the peak area of an external standard method, wherein the peak is not more than 0.2%.
The technical scheme of the invention is further improved as follows: the reference solution is prepared by precisely measuring SCH59566 as a reference, and quantitatively diluting with a diluent to obtain a solution containing 0.4 mu g of SCH59566 impurity per 1ml, namely the reference solution; the preparation method of the test solution comprises the steps of grinding ezetimibe simvastatin tablets into fine powder, putting the fine powder into a volumetric flask, adding a diluent, carrying out ultrasonic treatment for 30 minutes until the fine powder is dissolved, adding the diluent to dilute the mixture to a scale, shaking up, filtering, and taking a subsequent filtrate as the test solution.
The technical scheme of the invention is further improved as follows: the diluent is a mixed solution of 0.05mol/L sodium acetate buffer solution and acetonitrile according to the volume ratio of 20: 80.
The technical scheme of the invention is further improved as follows: the preparation method of the 0.05mol/L sodium acetate buffer solution comprises the steps of taking 3.0ml of glacial acetic acid, adding 750ml of water, shaking up, adjusting the pH value to 4.0 by using 50% sodium hydroxide solution, and adding water to 1000 ml.
The technical scheme of the invention is further improved as follows: 1 ezetimibe simvastatin tablet is dissolved in every 50ml of the test solution.
Due to the adoption of the technical scheme, the invention has the technical progress that:
the method for detecting the SCH59566 impurity content has strong specificity, the SCH59566 impurity peak can be separated from other impurity peaks by a base line, the peak type is better, and the impurity content is more accurately calculated.
Drawings
FIG. 1 is a map of system applicability in the examples;
FIG. 2 is a spectrum of a control solution in the examples;
FIG. 3 is a test solution profile of the test sample in the examples;
FIG. 4 is a solvent blank spectrum in the examples;
FIG. 5 is a graph of a test solution in comparative example 1;
FIG. 6 is a graph of a test solution in comparative example 2;
FIG. 7 is a graph of a test solution in comparative example 3;
FIG. 8 is a map of the test solution in comparative example 4.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
a method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets is characterized in that each ezetimibe simvastatin tablet contains 10mg of ezetimibe and 80mg of simvastatin, and high performance liquid chromatography is adopted to detect SCH59566 impurity content.
Wherein, the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecylsilane chemically bonded silica, specified as Waters XTerra RP18 (250X 4.6mm,5 μm);
mobile phase: the mobile phase A is a mixed solution of 0.1% phosphoric acid water solution, acetonitrile, methanol and tetrahydrofuran, and the mobile phase B is acetonitrile; wherein the volume ratio of the 0.1% phosphoric acid aqueous solution, the acetonitrile, the methanol and the tetrahydrofuran in the mobile phase A is 55:35:9: 1;
and (3) an elution mode: gradient elution; with particular reference to table 1 below, the following examples are given,
detection wavelength: 231 nm;
flow rate: 1.0 ml/min;
column temperature: 45 ℃;
sample loading amount: 10 μ l.
TABLE 1
The specific detection method comprises the following steps:
s1 preparing a reference solution and a test solution; wherein the reference solution is prepared by precisely measuring an appropriate amount of SCH59566 as a reference, and quantitatively diluting with diluent to obtain a solution containing about 0.4 μ g of SCH59566 per 1ml as a reference solution; the preparation of the test solution is that 10 tablets of ezetimibe simvastatin to be tested are taken and ground into fine powder, an appropriate amount of the fine powder (about 10mg of ezetimibe) is taken and precisely weighed, the fine powder is placed in 50ml for weighing, an appropriate amount of diluent is added, ultrasonic treatment is carried out for 30 minutes to dissolve the fine powder, the diluent is added for diluting to a scale, the mixture is shaken up and filtered, and a subsequent filtrate is taken as the test solution; the diluent is 0.05mol/L sodium acetate buffer (3.0 ml glacial acetic acid, 750ml water, shake, adjust pH to 4.0 with 50% sodium hydroxide solution, add water to 1000ml) -acetonitrile (20: 80); the specific dilution step is as follows:
1) and a reference stock solution: taking SCH59566 of about 10mg, putting into a 500ml volumetric flask, adding a diluent to dissolve and dilute to a scale, and shaking up to obtain the liquid.
2) And a reference solution: taking 2ml of the control solution stock solution, adding the diluent into a 100ml volumetric flask, dissolving and diluting to a scale, and shaking up to obtain the product.
3) And a test solution: precisely weighing a sample of about 800mg to 50ml in a measuring flask, adding a diluent to dilute the sample in a proper amount, performing ultrasonic treatment for 30 minutes to dissolve the sample, adding the diluent to dilute the sample to a scale, shaking up the sample, and filtering the sample to obtain a subsequent filtrate as a sample solution.
S2 precisely measuring 10 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram;
s3, calculating the peak consistent with the SCH59566 retention time in the chromatogram of the test solution according to the peak area of an external standard method, wherein the peak is not more than 0.2%.
Examples
1 Instrument and reagent
High performance liquid chromatography (Agilent Corp., model: 1260), electronic analytical balance (Mettler-Toliduo, model: XS 105).
Ezetimibe simvastatin tablets (self-made, lot number: 150601,150602,150603); SCH59566 control (Shanghai Mippo pharmaceutical science and technology Co., Ltd., batch No. 121120, content: 95.5%); phosphoric acid (analytical grade, chemical reagents of national drug group, ltd.); acetonitrile (chromatographic grade, CNW).
2 methods and results
2.1 chromatographic conditions
A chromatographic column: waters XTerra RP18 column (250X 4.6mm,5 μm); mobile phase A: 0.1% aqueous phosphoric acid-acetonitrile-methanol-tetrahydrofuran (55:35:9: 1); mobile phase B: acetonitrile; the flow rate is 1.0ml/min, the detection wavelength is 231nm, the column temperature is 45 ℃, and the sample injection amount is 10 mul; the gradient elution procedure is shown in table 2:
TABLE 2 gradient elution procedure
2.2 preparation of the solution
2.2.1 preparation of test solutions
Taking 10 tablets of the product, grinding into fine powder, precisely weighing about 800mg (about equivalent to 10mg of ezetimibe) of the fine powder into a 50ml measuring flask, adding a proper amount of solvent, dissolving by ultrasonic treatment for 30 minutes, adding the solvent to dilute to a scale, shaking uniformly, filtering, and taking the subsequent filtrate as a test solution.
2.2.2 preparation of control solutions
Taking 2ml of the control solution stock solution under the item of 2.2.3, adding a solvent into a volumetric flask of 100ml, dissolving and diluting to the scale, and shaking up to obtain the product.
2.2.3 preparation of reference stock solution
Taking SCH59566 of about 10mg to 500ml in a volumetric flask, adding a solvent to dissolve and dilute to a scale, and shaking up to obtain the liquid.
2.2.4 preparation of solvent
0.05mol/L sodium acetate buffer (3.0 ml glacial acetic acid, 750ml water, shake, adjust pH to 4.0 with 50% sodium hydroxide solution, add water to 1000ml) -acetonitrile (20: 80).
2.3 System applicability
Precisely weighing about 800mg of the fine powder of the product, measuring 1ml of SCH59566 reference stock solution (about 20 mug/ml), putting the SCH59566 reference stock solution into a 50ml measuring flask, adding a solvent, performing ultrasonic treatment at normal temperature for 30min to dissolve and dilute the SCH59566 to a scale, shaking up, filtering, taking a subsequent filtrate as a system applicability solution, wherein the separation degree of SCH59566 and an adjacent peak is not less than 1.5. The system applicability map is shown in figure 1, the reference map is shown in figure 2, the test sample map is shown in figure 3, and the solvent blank is shown in figure 4.
2.4 detection and quantitation limits
SCH59566 control samples were weighed at approximately 10mg each, diluted stepwise, and the quantitation limit of SCH59566 was 0.28ng when the S/N ratio was 10. The detection limit of SCH59566 is 0.09ng when the signal-to-noise ratio S/N is 3.
2.5 Linear relationship test
Taking a proper amount of SCH59566 reference substances, precisely weighing, adding a solvent to dissolve and dilute the reference substances to prepare a solution containing about 4 mu g/ml of SCH59566 per 1ml, and using the solution as a linear stock solution; precisely measuring the stock solution, diluting with solvent to obtain solutions containing 0.028 μ g, 0.2 μ g, 0.32 μ g, 0.4 μ g, 0.6 μ g and 0.8 μ g per 1ml, precisely measuring 10 μ l of liquid-phase injection chromatograph, and recording chromatogram. Linear regression was performed using the concentration of the control solution as the abscissa and the peak area as the ordinate, and the regression equation and the correlation coefficient were calculated, and the linear equation of SCH59566 was Y26789.7574 x +122.8385(r 0.9997).
2.6 precision test
The samples were injected in duplicate 6 times at 0.4. mu.g/ml at linear concentrations of SCH59566, respectively, and the results are shown in Table 3.
TABLE 3 results of sample introduction precision measurement
2.7 repeatability test
Ezetimibe simvastatin tablets (batch number: 150601) are taken to prepare 6 parts of test solution according to the method under the item '2.2.1', a control solution is prepared according to the method under the item '2.2.2', and sample injection analysis is carried out according to the chromatographic condition under the item '2.1'. The results are shown in Table 4.
TABLE 4 results of impurity repeatability tests
2.8 determination of the samples
3 batches of ezetimibe simvastatin tablets (batch No. 150601,150602,150603) were prepared as a test solution under item "2.2.1" and as a control solution under item "2.2.2". Sample injection was carried out under the chromatographic conditions of "2.1". The results are shown in Table 5, and the formula is calculated:
remarking: a. theDegradation products: peak area of degradation product SCH 59566; a. theControl: major peak area of SCH59566 control solution
CControl: SCH59566 control concentrations (mg/ml); wControl: w reference sample weighing (mg)
WFor supplying to: weighing sample amount (mg) of a test sample; wAverage: average tablet weight (mg)
n is diluted: dilution times of the test solution;
marking amount: labeled amount of Ezetimibe in test solution (10mg)
TABLE 5 measurement results of SCH59566 in ezetimibe simvastatin tablets
Comparative example 1
Comparative example 1 is a method for detecting the content of SCH59566 in ezetimibe simvastatin tablets in examples by using the detection method in patent document CN105319289A, and the specific steps are as follows:
phenyl hexyl silane bonded silica gel is used as a filling agent; gradient elution was carried out using 0.1% phosphoric acid solution-acetonitrile-methanol (48: 42: 10) as mobile phase A and acetonitrile as mobile phase B. The flow rate was 1.0ml per minute, the detection wavelength was 232nm, and the column temperature was 30 ℃.
TABLE 6 gradient elution procedure
The operation process is as follows: taking 10 ezetimibe simvastatin tablets (batch number: 150601), grinding into fine powder, precisely weighing an appropriate amount of fine powder (about 10mg of ezetimibe), adding 50ml of the fine powder, adding an appropriate amount of solvent, dissolving by ultrasonic treatment for 30 minutes, diluting the solvent to a scale, shaking uniformly, filtering, and taking a subsequent filtrate as a sample solution; precisely measure 30. mu.l of the solution, inject the solution into a liquid chromatograph, and record the chromatogram, as shown in FIG. 5.
Solvent: 0.1% phosphoric acid solution-acetonitrile-methanol (48: 42: 10)
As can be seen from the graph of FIG. 5, the SCH59566 had a peak time of 13.193min, a theoretical plate number of 7130, an impurity peak 12.929min associated with the plate, a degree of separation of 0.47, and no baseline separation, indicating that for ezetimibe simvastatin tablets (specification: each tablet contains 10mg of ezetimibe and 80mg of simvastatin), this method is not suitable for determining the SCH59566 content. In the example, as can be seen from the spectrum of fig. 3, the peak time of SCH59566 is 21.118min, and the theoretical plate number is: 9845, 19.669min of connected impurity peak, the separation degree is 2.01, the complete baseline separation can be realized, the specificity of the method is good, and the content of SCH59566 can be effectively detected.
Comparative example 2
Comparative example 2 is a comparative test of examples, specifically, the content of SCH59566 in zetimothiavas simvastatin tablets was measured using substantially the same chromatographic conditions as in comparative example 1, and different from comparative example 1, the mobile phase a of comparative example 2 was measured using 0.1% phosphoric acid solution-acetonitrile-methanol-tetrahydrofuran (48: 42: 9:1), the remaining chromatographic conditions and procedures were the same as in comparative example 1, and the chromatogram of the measurement results was shown in fig. 6.
As can be seen from the graph in FIG. 6, the SCH59566 had a peak time of 12.491min, a theoretical plate number of 7070, a peak of 12.248min associated with the impurity, and a degree of separation of 0.44, and failed to achieve baseline separation, indicating that the method is not suitable for determining the SCH59566 content for ezetimibe simvastatin tablets (specification: each tablet contains 10mg of ezetimibe and 80mg of simvastatin).
Comparative example 3
Comparative example 3 is a comparative test of examples, specifically, the content of SCH59566 in zetimothiavas simvastatin tablets was measured using substantially the same chromatographic conditions as in comparative example 2, and different from comparative example 2, the mobile phase a in comparative example 3 was measured using 0.1% phosphoric acid solution-acetonitrile-methanol-tetrahydrofuran (55:35:9:1), and the remaining chromatographic conditions and procedures were the same as in comparative example 2, and the chromatogram of the measurement results was shown in fig. 7.
As can be seen from the graph in FIG. 7, the SCH59566 had a peak time of 12.782min, a theoretical plate number of 8130, an associated impurity peak of 12.106min, a degree of separation of 0.52, and failed to be separated from the baseline, indicating that this method is not suitable for determining the SCH59566 content for ezetimibe simvastatin tablets (specification: each tablet contains 10mg ezetimibe and 80mg simvastatin).
Comparative example 4
Comparative example 4 is a comparative test of examples, specifically, the content of SCH59566 in zetimothiavas simvastatin tablets was measured using substantially the same chromatographic conditions as in comparative example 1, and in contrast to comparative example 1, the gradient elution in comparative example 3 was performed in the same manner as in examples, specifically, as shown in Table 7
TABLE 7 gradient elution procedure
The rest of the chromatographic conditions and the operation process are the same as those of comparative example 1, and the chromatogram of the detection result is shown in FIG. 8.
As can be seen from the graph in FIG. 8, the SCH59566 had a peak time of 11.781min, a theoretical plate number of 6609, a peak of associated impurities of 11.546min, and a degree of separation of 0.56, and no baseline separation was observed, indicating that this method is not suitable for determining the SCH59566 level for ezetimibe simvastatin tablets (specification: each tablet contains 10mg ezetimibe and 80mg simvastatin).
Claims (7)
1. A method for detecting SCH59566 impurity content in ezetimibe simvastatin tablets, wherein the specification of the ezetimibe simvastatin tablets is that each ezetimibe tablet contains 10mg of ezetimibe and 80mg of simvastatin, and the method is characterized in that: detecting the content of SCH59566 impurity by adopting high performance liquid chromatography; the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecylsilane chemically bonded silica;
mobile phase: the mobile phase A is a mixed solution of 0.1% phosphoric acid water solution, acetonitrile, methanol and tetrahydrofuran, and the mobile phase B is acetonitrile; the volume ratio of 0.1% phosphoric acid aqueous solution, acetonitrile, methanol and tetrahydrofuran in the mobile phase A is 55:35:9: 1;
and (3) an elution mode: gradient elution; the gradient elution is specifically that the volume ratio of the mobile phase A is 95% and the volume ratio of the mobile phase B is 5% within 0-25 min, the volume ratio of the mobile phase A is 0 and the volume ratio of the mobile phase B is 100% within 25-35 min, the volume ratio of the mobile phase A is 95% and the volume ratio of the mobile phase B is 5% within 35-45 min;
detection wavelength: 231 nm;
flow rate: 1.0 ml/min;
column temperature: 45 ℃;
sample introduction amount: 10 μ l.
2. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 1, wherein the method comprises the following steps: the column was model Waters XTerra RP18, 250X 4.6mm,5 μm.
3. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 1, wherein the method comprises the following steps: the detection method comprises the following steps:
s1 preparing a reference solution and a test solution;
s2 precisely measuring 10 μ l of each of the reference solution and the sample solution, respectively injecting into a liquid chromatograph, and recording chromatogram;
s3, calculating the peak consistent with the SCH59566 retention time in the chromatogram of the test solution according to the peak area of an external standard method, wherein the peak is not more than 0.2%.
4. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 3, wherein the method comprises the following steps: the reference solution is prepared by precisely measuring SCH59566 as a reference, and quantitatively diluting with a diluent to obtain a solution containing 0.4 mu g of SCH59566 impurity per 1ml, namely the reference solution; the preparation method of the test solution comprises the steps of grinding ezetimibe simvastatin tablets into fine powder, putting the fine powder into a volumetric flask, adding a diluent, carrying out ultrasonic treatment for 30 minutes until the fine powder is dissolved, adding the diluent to dilute the mixture to a scale, shaking up, filtering, and taking a subsequent filtrate as the test solution.
5. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 4, wherein the method comprises the following steps: the diluent is a mixed solution of 0.05mol/L sodium acetate buffer solution and acetonitrile according to the volume ratio of 20: 80.
6. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 5, wherein the method comprises the following steps: the preparation method of the 0.05mol/L sodium acetate buffer solution comprises the steps of taking 3.0ml of glacial acetic acid, adding 750ml of water, shaking up, adjusting the pH value to 4.0 by using 50% sodium hydroxide solution, and adding water to 1000 ml.
7. The method for detecting SCH59566 impurity content of ezetimibe simvastatin tablets according to claim 4, wherein the method comprises the following steps: 1 ezetimibe simvastatin tablet is dissolved in every 50ml of the test solution.
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