CN114280169B - Method for determining isomer in monabivir - Google Patents
Method for determining isomer in monabivir Download PDFInfo
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Abstract
The invention discloses an analysis method for measuring isomers in monabivalve, which adopts a reversed-phase high performance liquid chromatography, takes an acidic aqueous solution-organic phase with a certain proportion as a mobile phase, and separates and measures the monabivalve Wei Hemo monabivalve isomers. The method can effectively separate and detect the isomer of the monabivaliro, quantitatively determine the monabivaliro and the isomer thereof, realize the effective control of the purity of the monabivaliro, thereby improving the safety quality of medicines and providing a basis for formulating the quality standard of the monabivaliro bulk drug. The method has the advantages of high sensitivity, wide linear range, good specificity and repeatability and simple and convenient operation.
Description
Technical Field
The invention relates to the technical field of medicine analysis, in particular to a method for determining isomers in monabivavir.
Background
Morapiravir (Monnumpiravir), a small molecule cytidine antiviral drug developed by the United states pharmaceutical industry, giant head Shadong. The code is EIDD-2801 or MK4482, is a prodrug of an orally-taken bioactive ribonucleotide analogue beta-d-N4-hydroxyytidine (NHC; -1931), and can inhibit the replication of various RNA viruses. EIDD-2801 has broad-spectrum antiviral activity against influenza virus and various coronaviruses (e.g., SARS-chemical book CoV-2, mers-CoV, SARS-CoV) and thus has the potential to treat the novel coronavirus, COVID-19, as well as seasonal and pandemic influenza. Meanwhile, the medicine is a SARS-CoV2 polymerase inhibitor, and researches prove that in animal experiments, monumpiravir is used for treating ferrets infected with SARS-CoV2, and can effectively inhibit viruses and inhibit the growth of new coronaviruses within 24 hours, thereby inhibiting the transmission of the viruses. In fact, monabivir (Molnupiravir) for the treatment of new coronaries has been used in a number of countries with considerable success in terms of safety and tolerability. Evidence suggests that monabivir (Molnupiravir) helps to reduce the incidence of severe symptoms, reduce hospitalization rates, significantly alleviate symptoms, and reduce the risk of death.
Monapiravir (chemical name ((2R, 3S,4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxyamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) isobutyric acid methyl ester, molecular formula C 13 H 19 N 3 O 7 The molecular weight is: 329.31, which has the structural formula:
through analyzing the synthetic process route of the crude drug, the isomer generated in the process of the crude drug is ((2R, 3S,4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxylamine) -2-oxypyrimidine-1 (2H) -group) tetrahydrofuran-2-yl) methyl butyrate, and the structure is as follows:
in order to ensure the safety and effectiveness of monabivalve Wei Yaopin and directly influence the quality of the final product, the isomer generated in the synthesis process of the bulk drug is required to be researched and controlled, and the separation detection method of the isomer is not reported in the prior art, so that the isomer in the finished monabivalve is not convenient to control.
Disclosure of Invention
The invention aims to: the invention provides an analysis method for measuring isomers in monabivalve to fill the blank of the prior art, and the method can effectively separate the isomers, and has high impurity detection sensitivity, wide linear range and good specificity and repeatability.
The technical scheme is as follows: in order to solve the technical problems, the invention provides the following technical scheme:
a method for measuring isomer in monabivalve features that high-performance liquid chromatography is used, octadecylsilane chemically bonded silica gel is used as filler, mobile phase A is 0.1% aqueous solution of phosphoric acid (V/V), mobile phase B is the mixed solution of acetonitrile and methanol, the flow rate of mobile phase is 0.6-1.0 ml/min, gradient elution is used, the detector is ultraviolet absorption detector, the detection wavelength is 273-277 nm, and the temp of chromatographic column is 23-27 deg.C.
Wherein the isomer is: ((2R, 3S,4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxylamine) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) butanoic acid methyl ester having the structure:
in some embodiments, the volume ratio of acetonitrile to methanol in mobile phase B is 9:1.
In some embodiments, the detection wavelength is 275nm and the column temperature is 25 ℃.
In some embodiments, the mobile phase flow rate is 0.8mL/min.
In some embodiments, the chromatographic column used is an ACE Excel 5Super c18 column, specification 4.6mm x 250mm, packing particle size 5 μm.
In some embodiments, the gradient elution procedure employed is as follows:
| elution time (minutes) | Mobile phase a (%) | Mobile phase B (%) |
| 0.0 | 85.0 | 15.0 |
| 15.0 | 85.0 | 15.0 |
| 22.0 | 75.0 | 25.0 |
| 29.0 | 30.0 | 70.0 |
| 33.0 | 30.0 | 70.0 |
| 33.1 | 85.0 | 15.0 |
| 40.0 | 85.0 | 15.0 |
。
The method for measuring the isomer in the monabivavir provided by the invention comprises the following steps:
(1) Preparing a sample solution and a system applicability solution;
(2) Setting high performance liquid phase detection conditions: the chromatographic column is an ACE Excel 5Super C18 column, the specification is 4.6mm multiplied by 250mm, the filler particle diameter is 5 mu m, 0.1% phosphoric acid aqueous solution (V/V) is used as a mobile phase A, and the volume ratio is 9:1 acetonitrile-methanol as mobile phase B, gradient eluting at flow rate of 0.8ml/min, detection wavelength of 275nm, and chromatographic column temperature of 25deg.C;
(3) And respectively sucking the sample solution and the system applicability solution, and injecting the sample solution and the system applicability solution into a high performance liquid chromatograph for HPLC analysis.
The preparation method of the sample solution comprises the following steps: accurately weighing a proper amount of a test sample of the monabivaliro, adding a diluent (10% acetonitrile/water, V/V) for dissolving and diluting to obtain a solution containing 1mg/ml of the monabivaliro;
the preparation method of the system applicability solution comprises the following steps:
(S1) weighing a proper amount of ((2R, 3S,4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxylamine) -2-oxypyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methyl butyrate, adding a diluent (10% acetonitrile/water, V/V) to dissolve and dilute to prepare an impurity reference substance stock solution with 500 mug of impurity reference substance per 1 ml;
(S2) accurately weighing Moraxella Wei Shiliang, adding a diluent (10% acetonitrile/water, V/V) for dissolution, and taking the impurity reference stock solution to prepare a mixed solution containing 1 mug of impurity and 1mg of Moraxella per 1ml of impurity, thereby obtaining a system applicability solution.
In step (2), the gradient elution procedure is as follows:
the beneficial effects are that: the invention discloses a method for detecting isomers in monabivalve, which has the advantages of high sensitivity, good repeatability, accurate content measurement result and good specificity and linearity, and can be used for quality control of isomers in monabivalve. According to the invention, the Super inert ACE Excel 5Super C18 column with a wide pH value is selected, so that the product is effectively separated from the isomer, the high-sensitivity and high-accuracy qualitative and quantitative research on the isomer in the monabivalve is realized, and a foundation is laid for the quality control of the isomer in the monabivalve.
Drawings
FIG. 1 is a chromatogram of a hollow white solution of example 1;
FIG. 2 is a chromatogram of the sample solution of example 1;
FIG. 3 is a chromatogram of the system applicability solution in example 1.
Detailed Description
The drawings are for illustrative purposes only and are not to be construed as limiting the invention.
The method for detecting an isomer in monabivavir according to the present invention is described in further detail by way of examples.
Example 1: specificity test for isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol as mobile phase B, gradient elution was performed according to Table 1 below, at a flow rate of 0.8ml per minute; the detection wavelength is 275nm; the column temperature was 25 ℃.
TABLE 1 gradient elution
(2) Solution preparation
Test solution: taking a proper amount of a test sample of the monabivaliruses, precisely weighing, adding a diluting agent (10% acetonitrile/water, V/V) and carrying out ultrasonic treatment to dissolve and dilute the sample to prepare a solution containing about 1mg of the monabivaliruses per 1 ml.
Impurity control stock solution: an appropriate amount of the isomer impurity control was weighed, dissolved in a diluent (10% acetonitrile/water, V/V) and diluted to prepare a solution containing about 500 μg of each impurity per 1 ml.
System applicability solution: taking a proper amount of the monabivalve reference substance, precisely weighing, adding a diluting agent (10% acetonitrile/water, V/V) for ultrasonic dissolution, and taking a proper amount of the impurity reference substance stock solution to prepare a mixed solution containing about 1 mug of impurity and 1mg of monabivalve per 1 ml.
Blank solution: diluent (10% acetonitrile/water, V/V);
and precisely taking 5 mu l of each of the blank solution, the sample solution and the system applicability solution, injecting into a liquid chromatograph, and recording a chromatogram. Impurity peaks exist in the chromatogram of the sample solution, the impurity content is calculated according to an area normalization method, and the results are shown in tables 2-3. The patterns are shown in fig. 1, fig. 2 and fig. 3.
TABLE 2 results of the isomer determination proprietary test in monabivir
TABLE 3 test results of test solutions for substances of interest
(3) Results
The above specificity test results show that the blank solution has no interference by adopting the chromatographic conditions of the invention, and the monabivalirus and the isomer can be effectively separated, thus the method has good specificity.
Example 2: sensitivity test for isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol of 1 as mobile phase B, gradient elution was performed according to table 1 of example 1, at a flow rate of 0.8ml per minute; the detection wavelength is 275nm; the column temperature was 25 ℃.
(2) Solution preparation
Monabivavir control stock solution: taking a proper amount of a monabivalve reference substance, precisely weighing, adding a diluting agent (10% acetonitrile/water, V/V) and carrying out ultrasonic treatment to dissolve and dilute the monabivalve reference substance to prepare a solution with the concentration of about 500 mug of monabivalve per 1 ml.
Impurity control stock solution: an appropriate amount of the isomer impurity control was weighed, dissolved in a diluent (10% acetonitrile/water, V/V) and diluted to prepare a solution containing about 500 μg of each impurity per 1 ml.
Blank solution: diluent (10% acetonitrile/water, V/V);
and respectively precisely measuring a proper amount of each reference substance stock solution, gradually diluting and measuring by using a diluent (10% acetonitrile/water, V/V), taking the signal to noise ratio of about 10:1 as a quantitative limit, and examining the detection sensitivity of each impurity.
5 μl of each of the blank solution and each of the sensitive solutions was precisely taken, and injected into a liquid chromatograph, and the chromatograms were recorded, and the results are shown in Table 4.
TABLE 4 sensitivity investigation results
| Impurity name | Concentration (μg/ml) | Signal to noise ratio | Equivalent to the concentration percentage of the test sample |
| MoranabiLavir | 0.1053 | 12.3 | 0.011％ |
| Isomers of | 0.0985 | 15.5 | 0.010％ |
(3) Results
The sensitivity test results show that the method has good sensitivity by adopting the chromatographic conditions of the invention.
Example 3: linear test for isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol of 1 as mobile phase B, gradient elution was performed according to table 1 of example 1, at a flow rate of 0.8ml per minute; the detection wavelength is 275nm; the column temperature was 25 ℃.
(2) Solution preparation
Reference example 2 the preparation of the solutions of the monabivavir control stock solutions was followed by precise measurement of the appropriate amounts of the respective monabivavir control stock solutions, dilution with a diluent (10% acetonitrile/water, V/V) to give a range of concentrations, and the results are shown in table 5 as linear solutions of the respective components.
Table 5 Murray Wei Xianxing examination results
(3) Results
The linear test results show that the correlation coefficient r is more than or equal to 0.990, the y-axis intercept deviation is less than or equal to 25% in the concentration range of 0.1053 mug/ml to 5.1818 mug/ml by adopting the chromatographic condition of the invention, and the results show that the normal relation of the method is good.
Example 4: repeatability test of isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol of 1 as mobile phase B, gradient elution was performed according to table 1 of example 1, at a flow rate of 0.8ml per minute; the detection wavelength is 275nm; the column temperature was 25 ℃.
(2) Solution preparation
With reference to the applicability of the preparation system in the preparation of the solution of example 1 and the test solution, 6 parts of the test solution were prepared in parallel, and the results of the repeatability test were examined and are shown in Table 6.
Table 6 results of repeatability investigation
(3) Results
The repeatability test results show that the method has good repeatability by adopting the chromatographic conditions of the invention.
Example 5: accuracy test for isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol of 1 as mobile phase B, gradient elution was performed according to table 1 of example 1, at a flow rate of 0.8ml per minute; the detection wavelength is 275nm; the column temperature was 25 ℃.
(2) Solution preparation
9 parts of a test sample of the monabivaliro are precisely weighed, impurity reference substance solutions with the impurity limit of 50%, 100% and 150% are respectively added, and a diluent (10% acetonitrile/water, V/V) is added for dissolution and dilution to scale, so that the test sample solution is obtained. Recovery was calculated as impurity [ (measured amount-local amount)/addition amount ], and the results are shown in Table 7.
TABLE 7 accuracy investigation results
| Impurity name | Recovery range | Average recovery rate | RSD |
| Isomers of | 99.25％-106.45％ | 102.7％ | 2.62％ |
(3) Results
The accuracy test results show that the impurity recovery rate is between 80% and 120% by adopting the chromatographic conditions, the RSD is less than 10.0%, and the results show that the accuracy of the method is good.
Example 6: durability test for isomer determination in monabivir
(1) High performance liquid chromatography conditions
The chromatographic column is octadecylsilane chemically bonded silica gel column, the model is ACE Excel 5Super C18 column (4.6 mm multiplied by 250mm,5 μm), 0.1% phosphoric acid aqueous solution (V/V) is used as mobile phase A, and the volume ratio is 9: acetonitrile-methanol of 1 was used as mobile phase B, gradient elution was performed according to table 1 in example 1, and the durability of the chromatographic condition investigation method was changed according to the parameters of table 8.
Table 8 durability test parameters
| Chromatographic conditions | Specified value | Range of variation |
| Column temperature (. Degree. C.) | 25 | 23 and 27 |
| Flow rate (ml/min) | 0.8 | 0.6 and 1.0 |
| Wavelength (nm) | 275 | 273 and 277 |
(2) Solution preparation
The system applicability solutions and test solutions were prepared in the solution preparation of reference example 1, and the results are shown in Table 9.
Table 9 durability test results
(3) Results
The durability test results show that the minimum separation degree in the system applicability solution is more than 1.5 by properly changing chromatographic parameters (such as column temperature, flow rate and wavelength); under each chromatographic condition, the absolute difference of the impurity contents is less than 0.03% compared with the standard condition, which shows that the method has good durability.
The above examples of the present invention are merely illustrative of the present invention and are not intended to limit the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. Any modification, equivalent replacement, improvement, etc. which come within the spirit and principles of the invention are desired to be protected by the following claims.
Claims (7)
1. A method for measuring isomers in monabivir is characterized in that,
the structural formula of the monabivalve is shown as the formula (I):
the isomer is as follows: ((2R, 3S,4R, 5R) -3, 4-dihydroxy-5- (4- (hydroxyamino) -2-oxopyrimidin-1 (2H) -yl) tetrahydrofuranyl) butanoic acid methyl ester; the method is reverse phase high performance liquid chromatography;
the structural formula of the isomer is shown as a formula (II):
a chromatographic column with octadecylsilane chemically bonded silica as a filler is adopted, a mobile phase A is a phosphoric acid aqueous solution with the volume fraction of 0.1%, a mobile phase B is a mixed solution of acetonitrile and methanol, the flow rate of the mobile phase is 0.6-1.0 mL/min, gradient elution is adopted, a detector is an ultraviolet absorption detector, the detection wavelength is 273-277 nm, and the column temperature of the chromatographic column is 23-27 ℃;
the volume ratio of acetonitrile to methanol in the mobile phase B is 9:1;
the chromatographic column is an ACE Excel 5super C18 column, the specification is 4.6mm multiplied by 250mm, and the particle size of the filler is 5 mu m;
the gradient elution procedure is as follows:
2. the method for determining isomers in monabivavir according to claim 1, wherein the detection wavelength is 275nm and the column temperature of the chromatographic column is 25 ℃.
3. The method for determining isomers in monabivavir according to claim 1, wherein the mobile phase flow rate is 0.8mL/min.
4. The method for determining isomers in monabivavir according to claim 1, comprising the steps of:
(1) Preparing a sample solution and a system applicability solution;
(2) Setting high performance liquid phase detection conditions: the chromatographic column is an ACE Excel 5super C18 column, the specification is 4.6mm multiplied by 250mm, the filler particle diameter is 5 mu m, the volume fraction is 0.1% phosphoric acid aqueous solution as a mobile phase A, and the volume ratio is 9:1, wherein the acetonitrile and methanol mixed solution is a mobile phase B, the flow rate is 0.8ml/min, gradient elution is carried out, the detection wavelength is 275nm, and the column temperature of the chromatographic column is 25 ℃;
(3) And respectively sucking the sample solution and the system applicability solution, and injecting the sample solution and the system applicability solution into a high performance liquid chromatograph for HPLC analysis.
5. The method for determining isomers in monabivavir according to claim 4, wherein the preparation method of the test solution is as follows: accurately weighing a test sample of the monabivaliro, and adding a diluent to dissolve and dilute the test sample into a solution containing the monabivaliro of 1mg/ml, wherein the diluent is an acetonitrile water solution with the volume fraction of 10%.
6. The method for determining isomers in monabivavir according to claim 4, wherein the method for preparing the system-applicable solution comprises:
(S1) weighing ((2R, 3S,4R, 5R) -3, 4-dihydroxyl-5- (4- (hydroxylamine) -2-oxypyrimidin-1 (2H) -yl) tetrahydrofuran-2-yl) methyl butyrate, adding a diluent to dissolve and dilute to prepare an impurity reference substance stock solution with 500 mug of each 1ml of impurity reference substance;
(S2) precisely weighing the monabivalirus, adding a diluent for dissolution, and additionally taking the impurity reference substance storage solution to prepare a mixed solution containing 1 mug impurity and 1mg monabivalirus per 1ml so as to obtain a system applicability solution;
the diluent is acetonitrile water solution with volume fraction of 10%.
7. The method for determining isomers in monabivavir according to claim 4, wherein in step (2), the gradient elution procedure is as follows:
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| Engineered Ribosyl-1-Kinase Enables Concise Synthesis of Molnupiravir, an Antiviral for COVID-19;John A. McIntosh 等;ACS Cent. Sci.;第7卷;1980-1985 * |
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