CN109374782B - Method for separating and measuring related substances of empagliflozin bulk drug by using HPLC (high performance liquid chromatography) - Google Patents
Method for separating and measuring related substances of empagliflozin bulk drug by using HPLC (high performance liquid chromatography) Download PDFInfo
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- CN109374782B CN109374782B CN201811568040.0A CN201811568040A CN109374782B CN 109374782 B CN109374782 B CN 109374782B CN 201811568040 A CN201811568040 A CN 201811568040A CN 109374782 B CN109374782 B CN 109374782B
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Abstract
The invention provides a method for separating and measuring related substances of an epaliptin bulk drug by using HPLC (high performance liquid chromatography), which comprises the following steps of: octadecylsilane chemically bonded silica is used as a filling agent, water is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is carried out, the flow rate is 0.8-1.2 ml/min, the column temperature is 25-40 ℃, an ultraviolet detector is adopted to detect related substances of the empagliflozin bulk drug, and the detection wavelength of the ultraviolet detector is 205-230 nm. The method for separating and measuring related substances of the empagliflozin bulk drug by using HPLC comprehensively considers the comprehensive influence of an analytical column, a mobile phase, a gradient elution program, flow velocity and column temperature on separation and detection, so that the quality of the bulk drug is effectively controlled.
Description
Technical Field
The invention relates to the technical field of analytical chemistry, in particular to a method for separating and measuring related substances of an epaliptin bulk drug by using HPLC (high performance liquid chromatography).
Background
Empagliflozin (Empagliflozin, trade name Jardiance), a novel antidiabetic drug developed by the company brigreville and li, approved by the united states Food and Drug Administration (FDA) for marketing on day 01, 08/2014 for improving glycemic control in type 2 diabetic adult patients. Empagliflozin is a novel sodium-glucose cotransporter 2(SGLT2) inhibitor drug, and can increase glucose excretion by inhibiting reabsorption of glucose by kidneyThereby reducing the elevated blood glucose level of the diabetic. Molecular formula C23H27ClO7Molecular weight of 450.91, and structural formula as following formula (1):
in the preparation process of empagliflozin, a plurality of impurities are generated due to various factors such as starting materials, synthesis process, degradation and the like, wherein the impurities A, B, C, D and E are easy to generate in the synthesis process and are used as main inspected impurities in related substance projects, and the limit requirements are all less than 0.10 wt%.
Empagliflozin impurity A is a starting material of the synthesis process, and has a molecular formula: c17H16BrClO2Molecular weight: 367.66, the chemical formula is shown as the following formula (2):
empagliflozin impurity B is an intermediate IV with a molecular formula: c31H35ClO11Molecular weight: 619.06, the chemical formula is shown as the following formula (3):
empagliflozin impurity C is an intermediate II, and the molecular formula is as follows: c24H29ClO8Molecular weight: 480.93, the chemical formula is represented by the following formula (4):
empagliflozin impurity D is an isomer impurity corresponding to empagliflozin, and has a molecular formula:C23H27ClO7molecular weight: 450.91, the chemical formula is shown as the following formula (5):
empagliflozin impurity E is an impurity which is formed by the possible ring opening of a sugar fragment in the synthesis of empagliflozin, and has a molecular formula: c23H29ClO8Molecular weight: 468.9, the chemical formula is shown as the following formula (6):
in order to control the quality of the empagliflozin bulk drug, main components and impurities need to be controlled, and in the prior art, no analysis method suitable for quickly, simply and accurately analyzing and detecting related substances of the empagliflozin bulk drug exists. Therefore, further improvement and optimization needs exist for the determination method of related substances of empagliflozin bulk drug.
Disclosure of Invention
In order to overcome the technical problems in the prior art, the inventor of the invention has conducted a great deal of intensive research, and thus provides a method for separating and determining related substances in an empagliflozin bulk drug by using HPLC, which has the advantages of being fast, simple, convenient, high in sensitivity, accurate and reliable.
The technical scheme adopted by the invention is as follows:
a method for separating and measuring related substances of empagliflozin bulk drugs by using HPLC comprises the following steps: octadecylsilane chemically bonded silica is used as a filling agent, water is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is carried out, the flow rate is 0.8-1.2 ml/min, the column temperature is 25-40 ℃, an ultraviolet detector is adopted to detect related substances of the empagliflozin bulk drug, and the detection wavelength of the ultraviolet detector is 205-230 nm.
The method for separating and measuring related substances of empagliflozin bulk drug by using HPLC provided by the invention is characterized in that the length of a chromatographic column is 150 mm-250 mm, and is preferably 250 mm. This can improve the separation degree of the main peak from the impurity D peak and the impurity E peak.
The method for separating and measuring related substances in the empagliflozin bulk drug by using HPLC (high performance liquid chromatography) is characterized in that the particle size of the filling agent is 1.8-5 mu m, and preferably 5 mu m. This can further improve the degree of separation.
The invention relates to a method for separating and measuring related substances of an epaliptin bulk drug by using HPLC (high performance liquid chromatography), wherein the flow rate is 1.0ml/min, and the column temperature is 30 ℃. This improves the degree of separation between impurities.
The invention relates to a method for separating and measuring related substances of an epaliptin bulk drug by using HPLC, wherein the conditions of gradient elution are as follows:
| time in minutes | Mobile phase A, volume% | Mobile phase B, volume% |
| 0 | 70～80 | 20～30 |
| 15 | 55 | 45 |
| 30～40 | 5～15 | 85～95 |
| 55 | 5～15 | 85～95 |
The invention relates to a method for separating and measuring related substances of an epaliptin bulk drug by using HPLC, wherein the conditions of gradient elution are as follows:
| time in minutes | Mobile phase A, volume% | Mobile phase B, volume% |
| 0 | 75 | 25 |
| 15 | 55 | 45 |
| 30 | 10 | 90 |
| 55 | 10 | 90 |
The separation obtained is the best and the peak shape is the best.
The invention relates to a method for separating and measuring related substances of empagliflozin bulk drug by using HPLC, wherein the detection wavelength of an ultraviolet detector is 224 nm. This can improve the detection sensitivity of impurities.
Compared with the prior art, the invention has the following beneficial effects:
the method for separating and measuring related substances of the empagliflozin bulk drug by using HPLC comprehensively considers the comprehensive influence of an analytical column, a mobile phase, a gradient elution program, flow rate and column temperature on separation and detection, so that the detection result is optimized, the impurities A, B, C, D and E in the empagliflozin bulk drug can be quickly and efficiently separated under the same chromatographic condition, and the quality of the bulk drug can be effectively controlled.
Drawings
FIG. 1 is a chromatogram of a blank solution tested under the conditions of example 1 in accordance with the present invention;
FIG. 2 is a chromatogram of a system suitability solution tested under the conditions of example 1 in the present invention;
FIG. 3 is a chromatogram of a limiting quantitation solution detected under the conditions of example 1 in the present invention;
FIG. 4 is a chromatogram of a test solution tested under the conditions of example 1 in accordance with the present invention;
FIG. 5 is a chromatogram of a detection limiting solution detected under the conditions of example 1 in the present invention;
FIG. 6 is a chromatogram of a blank solution tested under the conditions of example 2 in accordance with the present invention;
FIG. 7 is a chromatogram of a test solution tested under the conditions of example 2 in accordance with the present invention;
FIG. 8 is a chromatogram of a system suitability solution tested under the conditions of example 2 in the present invention;
FIG. 9 is a chromatogram of a limiting quantitation solution detected under the conditions of example 2 in the present invention;
FIG. 10 is a chromatogram of a detection-limiting solution detected under the conditions of example 2 in the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention. The reagents and instruments used are not indicated by manufacturers, and conventional products can be obtained commercially.
The empagliflozin bulk drug and the impurity reference substance used in the embodiment of the invention are prepared by the inventor.
Example 1
The chromatographic conditions were as follows:
a chromatographic column: agilent 5TC-C18(2) 250X 4.6mm
Mobile phase A: water (W)
Mobile phase B: acetonitrile
Column temperature: 30 deg.C
Flow rate: 1.0ml/min
Detection wavelength: 224nm
Sample introduction amount: 10 μ L
The gradient elution procedure was:
TABLE 1 gradient elution procedure
| Time in minutes | Mobile phase A, volume% | Mobile phase B, volume% |
| 0 | 75 | 25 |
| 15 | 55 | 45 |
| 30 | 10 | 90 |
| 55 | 10 | 90 |
Solution preparation:
impurity reference stock solution: precisely weighing about 12.5mg of impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance and impurity E reference substance, placing in a 25ml measuring flask, adding diluent, dissolving and diluting to scale, and shaking; the diluent is as follows: acetonitrile-water (50:50) (V/V).
System applicability solution: precisely weighing about 50mg of empagliflozin working reference substance, placing into a 100ml measuring flask, precisely adding 1ml of impurity reference substance storage solution into the 100ml measuring flask, adding diluent to dilute to scale, and shaking up to obtain the final product.
Test solution: weighing about 50mg of empagliflozin raw material medicine, accurately weighing, placing in a 100ml measuring flask, adding a diluent to dissolve and dilute to a scale, and shaking up.
Empagliflozin reference stock solution: precisely weighing about 50mg of empagliflozin working reference substance, placing into a 100ml measuring flask, adding a diluent to dissolve and dilute to a scale, and shaking up to obtain the empagliflozin working reference substance.
Quantitative limiting solution: precisely measuring the impurity reference substance storage solution and the eprazimutm reference substance storage solution in measuring bottles of 1ml to 100ml respectively, adding a diluent to dilute to scales, shaking up, precisely measuring 1ml to 25ml, adding the diluent to dilute to scales, and shaking up to obtain the water quality control agent.
Detection limiting solution: precisely measuring 5ml of the quantitative limiting solution, putting the quantitative limiting solution into a 10ml measuring flask, adding a diluent to dilute to a scale, and shaking up to obtain the product.
And (3) determination: respectively injecting blank solution (namely diluent), system applicability solution, quantitative limiting solution, sample solution and detection limiting solution into a high performance liquid chromatograph for detection, using octadecylsilane chemically bonded silica as a filler (the particle size is 5 mu m, the inner diameter of a column is 4.6mm, the length of a chromatographic column is 250mm), detecting according to a gradient elution program in Table 1, and recording a chromatogram.
Chromatograms of the blank solution (i.e., diluent), the system applicability solution, the quantification limit solution, the sample solution and the detection limit solution are respectively shown in fig. 1, 2, 3, 4 and 5, and it can be seen that fig. 1 shows that the blank does not interfere with the impurity inspection; FIG. 2 shows that the separation degree between each impurity and empagliflozin is good, and the applicability map data of the concrete empagliflozin system is shown in Table 2; FIG. 3 shows empagliflozin and the quantitative limits of impurity A, impurity B, impurity C, impurity D and impurity E are 0.04 wt%, 0.04 wt% and 0.04 wt%, respectively; FIG. 4 shows that impurities A, B, C, D and E are not detected in a self-made eprazifom sample, and other single impurities are detected to be below 0.1 wt%; FIG. 5 shows that the detection limits of empagliflozin and impurity A, impurity B, impurity C, impurity D and impurity E are 0.02 wt%, 0.02 wt% and 0.02 wt%, respectively, which are lower than the limit of each impurity by 0.10 wt%; the method has high detection sensitivity.
TABLE 2 data Table of empagliflozin system applicability profiles in example 1
Example 2
The chromatographic conditions were as follows:
a chromatographic column: agilent 5TC-C18(2) 250X 4.6mm
Mobile phase A: water (W)
Mobile phase B: acetonitrile
Column temperature: 30 deg.C
Flow rate: 1.0ml/min
Detection wavelength: 224nm
Sample introduction amount: 10 μ l
The gradient elution procedure was:
TABLE 3 gradient elution procedure
| Time in minutes | Mobile phase A, volume% | Mobile phase B, |
| 0 | 80 | 20 |
| 15 | 55 | 45 |
| 30 | 15 | 85 |
| 55 | 15 | 85 |
Solution preparation:
impurity reference stock solution: precisely weighing about 12.5mg of impurity A reference substance, impurity B reference substance, impurity C reference substance, impurity D reference substance and impurity E reference substance, placing in a 25ml measuring flask, adding diluent, dissolving and diluting to scale, and shaking; the diluent is as follows: acetonitrile-water (50:50) (V/V).
System applicability solution: precisely weighing about 50mg of empagliflozin working reference substance, placing into a 100ml measuring flask, precisely adding 1ml of impurity reference substance storage solution into the 100ml measuring flask, adding diluent to dilute to scale, and shaking up to obtain the final product.
Test solution: weighing about 50mg of empagliflozin raw material medicine, accurately weighing, placing in a 100ml measuring flask, adding a diluent to dissolve and dilute to a scale, and shaking up.
Empagliflozin reference stock solution: precisely weighing about 50mg of empagliflozin working reference substance, placing into a 100ml measuring flask, adding a diluent to dissolve and dilute to a scale, and shaking up to obtain the empagliflozin working reference substance.
Quantitative limiting solution: precisely measuring the impurity reference substance storage solution and the eprazimutm reference substance storage solution in measuring bottles of 1ml to 100ml respectively, adding a diluent to dilute to scales, shaking up, precisely measuring 1ml to 25ml, adding the diluent to dilute to scales, and shaking up to obtain the water-soluble anti-cancer drug.
Detection limiting solution: precisely measuring 5ml of the quantitative limiting solution, putting the quantitative limiting solution into a 10ml measuring flask, adding a diluent to dilute to a scale, and shaking up to obtain the product.
And (3) determination: respectively injecting blank solution (namely diluent), system applicability solution, quantitative limiting solution, sample solution and detection limiting solution into a high performance liquid chromatograph for detection, using octadecylsilane chemically bonded silica as a filler (the particle size is 5 mu m, the inner diameter of a column is 4.6mm, the length of a chromatographic column is 250mm), detecting according to a gradient elution program shown in Table 3, and recording a chromatogram.
Chromatograms of the blank solution (i.e., diluent), the test sample solution, the system applicability solution, the quantification limit solution, and the detection limit solution are shown in fig. 6, 7, 8, 9, and 10, respectively, and it can be seen that fig. 6 shows that the blank does not interfere with the impurity inspection; FIG. 7 shows that impurities A, B, C, D and E are not detected in a self-made eprazifom sample, and other single impurities are detected to be below 0.1 wt%; FIG. 8 shows that the separation degree between each impurity and empagliflozin is good, and the applicability map data of the concrete empagliflozin system is shown in Table 4; FIG. 9 shows empagliflozin and the quantitative limits of impurity A, impurity B, impurity C, impurity D and impurity E are 0.04 wt%, 0.04 wt% and 0.04 wt%, respectively; FIG. 10 shows that the detection limits of empagliflozin and impurity A, impurity B, impurity C, impurity D and impurity E are 0.02 wt%, and 0.02 wt%, respectively, which are lower than the limit of each impurity by 0.10 wt%; the method has high detection sensitivity.
Table 4 data table of empagliflozin system applicability profiles in example 2
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (6)
1. A method for separating and measuring related substances of empagliflozin bulk drugs by using HPLC is characterized in that: the method comprises the following steps: using octadecylsilane chemically bonded silica as a filling agent, using water as a mobile phase A and acetonitrile as a mobile phase B to carry out gradient elution, wherein the flow rate is 0.8-1.2 ml/min, the column temperature is 25-40 ℃, an ultraviolet detector is adopted to detect related substances of the empagliflozin bulk drug, and the detection wavelength of the ultraviolet detector is 205-230 nm;
the conditions of the gradient elution are as follows:
Or the conditions of the gradient elution are:
The related substances of the empagliflozin bulk drug comprise an impurity A, an impurity B, an impurity C, an impurity D and an impurity E, wherein the chemical structural formulas of the impurity A, the impurity B, the impurity C, the impurity D and the impurity E are respectively as follows:
2. the method for separating and measuring related substances in epaliptin bulk drug by HPLC according to claim 1, which is characterized in that: the length of the chromatographic column is 150 mm-250 mm.
3. The method for separating and measuring related substances in epaliptin bulk drug by HPLC according to claim 1, which is characterized in that: the column length was 250 mm.
4. The method for separating and measuring related substances in epaliptin bulk drug by HPLC according to claim 1, which is characterized in that: the particle size of the filler is 5 mu m.
5. The method for separating and measuring related substances in epaliptin bulk drug by HPLC according to claim 1, which is characterized in that: the flow rate was 1.0ml/min and the column temperature was 30 ℃.
6. The method for separating and determining related substances of empagliflozin bulk drug according to any one of claims 1 to 5, characterized in that: the detection wavelength of the ultraviolet detector is 224 nm.
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| CN111983054B (en) * | 2020-07-28 | 2022-06-07 | 安徽联创生物医药股份有限公司 | Method for separating and measuring related substances of empagliflozin intermediate by using HPLC (high performance liquid chromatography) |
| CN114264747A (en) * | 2021-12-27 | 2022-04-01 | 浙江海翔药业股份有限公司 | High performance liquid chromatography detection method for empagliflozin intermediate and related substances thereof |
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