CN112255352A - Method for detecting related substances of esomeprazole sodium for injection - Google Patents
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Abstract
The invention discloses a method for detecting related substances of esomeprazole sodium for injection, which specifically comprises the following steps: step S1: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase A; step S2: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase B; step S3: carrying out gradient elution on the mobile phase A prepared in the step S1 and the mobile phase B prepared in the step S2 at the detection wavelength of 302nm and the column temperature of 30 ℃; the sample solution used in gradient elution is obtained by dissolving an esomeprazole sodium sample in a diluent, and quantitatively diluting the solution to prepare the sample solution containing about 1mg per 1 mL.
Description
Technical Field
The invention belongs to the field of medicine detection, and particularly relates to a method for detecting related substances of esomeprazole sodium for injection.
Background
Esomeprazole sodium (great name: esomeprazole sodium) belongs to a proton pump inhibitor, the Proton Pump Inhibitor (PPI) is the first choice drug for treating acid-related diseases such as peptic ulcer, gastroesophageal reflux disease and the like, 5 kinds of PPI are currently and commonly used clinically, omeprazole, lansoprazole, rabeprazole, pantoprazole and esomeprazole are used as the first PPI drug, the curative effect of the omeprazole for treating the acid-related diseases is agreed, esomeprazole is an S-isomer of omeprazole, gastric acid secretion is reduced through a specific targeting action mechanism, the esomeprazole is a specific inhibitor of a proton pump in a parietal cell, and compared with omeprazole, the omeprazole has higher bioavailability and more consistent pharmacokinetics, and is obviously superior to other proton pump inhibitors such as lansoprazole, pantoprazole, rabeprazole and the like in the aspect of controlling gastric acid.
The esomeprazole sodium is unstable in an acid solution and under the illumination condition, and can be slowly degraded to generate impurities under the high-temperature condition, the increase of the content of the impurities can cause serious adverse reaction, and related impurities in the product need to be strictly monitored in order to ensure the safety and effectiveness of the product, so that a related substance detection method is an important index for controlling the quality of the product.
At present, the detection method of related substances of the variety recorded in pharmacopoeias of various countries has the defects of low sensitivity, less impurity detection and the like, so that the development of a method which can effectively detect and separate a plurality of impurities, has high sensitivity and good durability and is easy to operate is very important.
Disclosure of Invention
The invention aims to provide a method for detecting related substances of esomeprazole sodium for injection.
The technical problems to be solved by the invention are as follows:
the existing detection method for the esomeprazole sodium related substance for injection has low detection sensitivity, so that the detection accuracy is reduced, and meanwhile, the existing reference detection method can detect less impurities, so that the eluted sample contains impurities.
The purpose of the invention can be realized by the following technical scheme:
a method for detecting related substances of esomeprazole sodium for injection specifically comprises the following steps:
step S1: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase A;
step S2: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase B;
step S3: and (3) carrying out gradient elution on the mobile phase A prepared in the step S1 and the mobile phase B prepared in the step S2 at the detection wavelength of 302nm and the column temperature of 30 ℃.
Further, the volume ratio of the deionized water to the phosphate buffer and the acetonitrile in the mobile phase a in the step S1 is 8:1: 1.
Further, the volume ratio of the deionized water to the phosphate buffer and the acetonitrile in the mobile phase B in the step S2 is 19:1: 80.
Further, the phosphate buffer solution of steps S1 and S2 is prepared by the following steps: 0.0052mol of sodium dihydrogen phosphate and 0.032mol of disodium hydrogen phosphate were dissolved in distilled water, the pH was adjusted to 7.6 with a 1mol/L sodium hydroxide solution, and then the volume was adjusted to 1000mL with deionized water.
Further, the gradient elution described in step S3 used an elution column of octadecylsilane bonded silica gel, which was a Waters XTerra MS C18, 4.6mm X150 mm, 3.5 μm.
Further, the gradient elution procedure described in step S3 is specifically 0min, 95% mobile phase a, 5% mobile phase B; 5min, 95% mobile phase A, 5% mobile phase B; 15min, 80% mobile phase a, 20% mobile phase B; 25min, 75% mobile phase a, 25% mobile phase B; 30min, 75% mobile phase a, 25% mobile phase B; 45min, 0% mobile phase a, 100% mobile phase B; 49min, 0% mobile phase a, 100% mobile phase B; 50min, 95% mobile phase A, 5% mobile phase B; 60min, 95% mobile phase a, 5% mobile phase B.
Further, the sample solution for gradient elution described in step S3 is prepared by the following steps: and mixing the esomeprazole sodium sample and the diluent until the esomeprazole sodium sample is completely dissolved, and quantitatively diluting to prepare a test solution containing about 1mg in each 1 mL.
Further, the diluent is a mixture of phosphate buffer and methanol at a volume ratio of 3:2, and the phosphate buffer is the same as the phosphate buffer described in step S1 and step S2.
The invention has the beneficial effects that: the invention provides a method for detecting esomeprazole sodium related substances for injection, which can well separate process impurities, degradation impurities and main components, and has the advantages of high sensitivity, good durability and simple and convenient operation.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a system suitability result;
FIG. 2 is a line graph of a methodological investigation of a portion of the impurity analysis method;
FIG. 3 is a line diagram of a methodology investigation of a partial impurity analysis method.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A method for detecting related substances of esomeprazole sodium for injection specifically comprises the following steps:
step S1: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle according to the volume ratio of 8:1:1, and mixing uniformly to obtain a mobile phase A;
step S2: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle according to the volume ratio of 19:1:80, and mixing uniformly to obtain a mobile phase B;
step S3: and (3) carrying out gradient elution on the mobile phase A prepared in the step S1 and the mobile phase B prepared in the step S2 at the detection wavelength of 302nm and the column temperature of 30 ℃.
The phosphate buffer solution of the steps S1 and S2 is prepared by the following steps: 0.0052mol of sodium dihydrogen phosphate and 0.032mol of disodium hydrogen phosphate were dissolved in distilled water, the pH was adjusted to 7.6 with a 1mol/L sodium hydroxide solution, and then the volume was adjusted to 1000mL with deionized water.
The elution with gradient described in step S3 was performed using an octadecylsilane bonded silica elution column model Waters XTerra MS C18, 4.6mm X150 mm, 3.5 μm.
The gradient elution procedure described in step S3 is specifically 0min, 95% mobile phase a, 5% mobile phase B; 5min, 95% mobile phase A, 5% mobile phase B; 15min, 80% mobile phase a, 20% mobile phase B; 25min, 75% mobile phase a, 25% mobile phase B; 30min, 75% mobile phase a, 25% mobile phase B; 45min, 0% mobile phase a, 100% mobile phase B; 49min, 0% mobile phase a, 100% mobile phase B; 50min, 95% mobile phase A, 5% mobile phase B; 60min, 95% mobile phase a, 5% mobile phase B.
The sample solution for gradient elution described in step S3 is prepared by the steps of: and mixing the esomeprazole sodium sample and the diluent until the esomeprazole sodium sample is completely dissolved, and quantitatively diluting to prepare a test solution containing about 1mg in each 1 mL.
The diluent is formed by mixing phosphate buffer solution and methanol according to the volume ratio of 3:2, and the phosphate buffer solution is the same as the phosphate buffer solution in the steps S1 and S2.
Example 2
A method for detecting related substances of esomeprazole sodium for injection specifically comprises the following steps:
step S1: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle according to the volume ratio of 8:1:1, and mixing uniformly to obtain a mobile phase A;
step S2: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle according to the volume ratio of 19:1:80, and mixing uniformly to obtain a mobile phase B;
step S3: and (3) carrying out gradient elution on the mobile phase A prepared in the step S1 and the mobile phase B prepared in the step S2 at the detection wavelength of 302nm, the column temperature of 30 ℃ and the flow rate of 1.0 mL/min.
The gradient elution procedure described in step S3 is specifically 0min, 95% mobile phase a, 5% mobile phase B; 5min, 95% mobile phase A, 5% mobile phase B; 15min, 80% mobile phase a, 20% mobile phase B; 25min, 75% mobile phase a, 25% mobile phase B; 30min, 75% mobile phase a, 25% mobile phase B; 45min, 0% mobile phase a, 100% mobile phase B; 49min, 0% mobile phase a, 100% mobile phase B; 50min, 95% mobile phase A, 5% mobile phase B; 60min, 95% mobile phase a, 5% mobile phase B.
System applicability solution preparation:
taking impurity A (2-mercapto-5-methoxy-1H-benzimidazole), impurity C (5-methoxy-2- ((4-methoxy-3, 5-dimethylpyridine-2-yl) methyl) thio) -1H-benzo [ D ] imidazole), impurity D (5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfonyl ] -1H-benzimidazole), impurity H (1, 4-dihydro-1- (5-methoxy-1H-benzimidazole-2-yl) -3, 5-dimethyl-4-oxo-2-pyridine carboxylic acid), Respectively adding 10mg of impurity I (5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1-methylbenzimidazole and 6-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfinyl ] -1-methylbenzimidazole) into a 50mL volumetric flask, adding 30mL of acetonitrile and 15mL of purified water, ultrasonically dissolving, fixing the volume of the acetonitrile, and shaking up to prepare an impurity stock solution 1-5; taking 10mg of impurity J (2- [ [ (5-methoxy-1H-benzimidazole-2-yl) sulfinyl ] methyl ] -3, 5-dimethyl-4 (1H) -1-pyridone), placing the 10mg in a 50mL measuring flask, firstly adding about 40mL of dichloromethane, then adding about 5mL of methanol, shaking to dissolve, adding dichloromethane to fix the volume, shaking uniformly to obtain an impurity stock solution 6, weighing about 10mg of an omeprazole reference substance, precisely weighing, placing the omeprazole reference substance in a 10mL measuring flask, adding about 7mL of a diluent to dissolve, taking 0.2mL of each impurity stock solution 1-6, adding a diluent to fix the volume, shaking uniformly to prepare a mixed solution containing about 1mg of omeprazole in each 1mL and about 2ug of each impurity, and preparing the system applicability solution 1-6.
Preparing a test sample:
and (3) mixing the esomeprazole sodium sample and the diluent until the esomeprazole sodium sample is completely dissolved, transferring the mixture to a 200mL measuring flask, and adding the diluent to dilute the mixture to the scale.
0.2% control solution:
taking a measuring flask of 0.2mL to 100mL of the test article, adding a diluent to a constant volume, and shaking up.
Sensitivity solution:
an appropriate amount of the sample was diluted with a diluent to prepare a solution containing about 0.5. mu.g of the sample per 1mL as a sensitive solution.
Injecting 20 mul of system applicability solution into a liquid chromatograph, wherein the retention time of an omeprazole peak is 25-26 minutes, the separation degree of the omeprazole peak and an impurity D peak is more than 1.5, and the separation degree of other known impurities is more than 1.5; injecting 20 mu l of the sensitivity solution into a liquid chromatograph, and recording a chromatogram, wherein the signal-to-noise ratio of the peak height of the main component is more than 10; measuring 20 mul of each of the test solution and the control solution, injecting into a liquid chromatograph, and recording the chromatogram; if an impurity peak exists in a chromatogram of a test solution, calculating the content of the impurity according to a main component self-contrast method multiplied by a correction factor, wherein the content of the impurity is in accordance with the corresponding limit regulation; peaks smaller than 0.25 times (0.05%) of the area of the main peak of the control solution in the chromatogram of the test solution were ignored.
And (3) respectively taking 20 mu L of diluent, blank auxiliary material solution, sensitivity solution, system applicability solution, test sample solution and 0.2% control solution, injecting into a liquid chromatograph according to the sample injection sequence shown in the following table, and recording the chromatogram.
| Name (R) | Number of sample introduction needles |
| 1. Blank solvent (Diluent) | At least 1 needle |
| 2. Blank auxiliary material | At least 1 needle |
| 3. Sensitive solution | 1 needle |
| 4. System applicability solution | 1 needle |
| 5. First batch of test solution | 1 needle |
| 6. Second batch of test articles | 1 needle |
| 7. 0.2% control solution for first batch of test sample | 1 needle |
| 8. Second batch of 0.2% control solution | 1 needle |
The system applicability result is shown in figure 1, the solvent does not interfere the measurement of related substances of known impurities in the test solution, the separation between the impurities and the main peak is good, and the tailing factors and the number of theoretical plates meet the measurement requirements of the related substances.
Example 3
The methodology of each impurity analysis method is examined, and the impurity V is the same as the impurity A, the impurity I is the same as the impurity D, the impurity III is the same as the impurity I, and the impurity IV is the same as the impurity J.
The line diagrams of each impurity are shown in fig. 2 and 3; as is clear from fig. 2 and 3, the linearity of each impurity is good.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (8)
1. A method for detecting related substances of esomeprazole sodium for injection is characterized by comprising the following steps: the method specifically comprises the following steps:
step S1: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase A;
step S2: adding deionized water, phosphate buffer solution and acetonitrile into a stirring kettle, and mixing uniformly to obtain a mobile phase B;
step S3: and (3) carrying out gradient elution on the mobile phase A prepared in the step S1 and the mobile phase B prepared in the step S2 at the detection wavelength of 302nm and the column temperature of 30 ℃.
2. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the volume ratio of the deionized water to the phosphate buffer to the acetonitrile in the mobile phase A in the step S1 is 8:1: 1.
3. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the volume ratio of the deionized water to the phosphate buffer to the acetonitrile in the mobile phase B in the step S2 is 19:1: 80.
4. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the phosphate buffer solution of the steps S1 and S2 is prepared by the following steps: 0.0052mol of sodium dihydrogen phosphate and 0.032mol of disodium hydrogen phosphate were dissolved in distilled water, the pH was adjusted to 7.6 with a 1mol/L sodium hydroxide solution, and then the volume was adjusted to 1000mL with deionized water.
5. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the elution with gradient described in step S3 was performed using an octadecylsilane bonded silica elution column model Waters XTerra MS C18, 4.6mm X150 mm, 3.5 μm.
6. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the gradient elution procedure described in step S3 is specifically 0min, 95% mobile phase a, 5% mobile phase B; 5min, 95% mobile phase A, 5% mobile phase B; 15min, 80% mobile phase a, 20% mobile phase B; 25min, 75% mobile phase a, 25% mobile phase B; 30min, 75% mobile phase a, 25% mobile phase B; 45min, 0% mobile phase a, 100% mobile phase B; 49min, 0% mobile phase a, 100% mobile phase B; 50min, 95% mobile phase A, 5% mobile phase B; 60min, 95% mobile phase a, 5% mobile phase B.
7. The method for detecting the esomeprazole sodium related substance for injection according to claim 1, wherein the method comprises the following steps: the sample solution for gradient elution described in step S3 is prepared by the steps of: and mixing the esomeprazole sodium sample and the diluent until the esomeprazole sodium sample is completely dissolved, and quantitatively diluting to prepare a test solution containing about 1mg in each 1 mL.
8. The method for detecting the esomeprazole sodium related substance for injection according to claim 7, wherein the method comprises the following steps: the diluent is formed by mixing phosphate buffer solution and methanol according to the volume ratio of 3:2, and the phosphate buffer solution is the same as the phosphate buffer solution in the steps S1 and S2.
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| CN113009028A (en) * | 2021-02-26 | 2021-06-22 | 海南葫芦娃药业集团股份有限公司 | Method for detecting related substances of omeprazole sodium for injection |
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