CN112557541B - Detection method of maropiptan citrate and related substances thereof - Google Patents
Detection method of maropiptan citrate and related substances thereof Download PDFInfo
- Publication number
- CN112557541B CN112557541B CN202011424925.0A CN202011424925A CN112557541B CN 112557541 B CN112557541 B CN 112557541B CN 202011424925 A CN202011424925 A CN 202011424925A CN 112557541 B CN112557541 B CN 112557541B
- Authority
- CN
- China
- Prior art keywords
- citrate
- impurity
- solution
- related substances
- mobile phase
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
-
- 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
- G01N30/30—Control of physical parameters of the fluid carrier of temperature
-
- 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
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
-
- 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
-
- 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
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
-
- 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
- G01N30/8624—Detection of slopes or peaks; baseline correction
- G01N30/8631—Peaks
- G01N30/8634—Peak quality criteria
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
-
- 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
- G01N30/32—Control of physical parameters of the fluid carrier of pressure or speed
- G01N2030/324—Control of physical parameters of the fluid carrier of pressure or speed speed, flow rate
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/884—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample organic compounds
-
- 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
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
- G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities
Landscapes
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Quality & Reliability (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
Abstract
The invention relates to the technical field of drug analysis, in particular to a detection method of maririptan citrate and related substances thereof. The detection method is a high performance liquid chromatography, and can realize effective separation between main components and known impurities by optimizing the solvent of a solution to be detected and chromatographic conditions, and accurately, qualitatively and quantitatively detect the maropiptan citrate and impurity conditions thereof. The detection method disclosed by the invention has the advantages of good chromatographic peak separation effect, high sensitivity, good accuracy and reproducibility, simplicity and convenience in operation, fills the blank in the field of detection of related substances of the maropritan citrate, provides reliable guarantee for improving and better controlling the quality of the maropritan citrate product, and has wide application prospect.
Description
Technical Field
The invention relates to the technical field of drug analysis, in particular to a detection method of maririptan citrate and related substances thereof.
Background
The acid Citrate malariptan (English name: Marovitant Citrate; CAS number: 147116-67-4) is a neurokinin (NK1) receptor antagonist, can block the combination of a substance P (neurotransmitter related to emesis) and the receptor, can effectively inhibit central nervous emesis, peripheral nervous emesis and emesis caused by chemical factors, is a first medicament for preventing and treating canine severe emesis and motion sickness, is also a first approved medicament for treating canine motion sickness, has definite curative effect, has the advantages of quick absorption, high bioavailability, lasting medicinal effect, high safety and the like, and has good clinical application value and market prospect.
Impurities such as initial raw materials, intermediates, byproducts and the like can be introduced in the synthesis process of the citric acid maropiptan, so that a corresponding detection method must be established so as to control the content of the impurities to ensure the safety of medication. However, at present, the methods for detecting the substances related to the marzipan citrate are not included in the United states Pharmacopeia, European Pharmacopeia, Japanese Pharmacopeia and Chinese Pharmacopeia, and the methods for detecting the substances related to the marzipan citrate reported in the related documents are not detected. However, the safety of related substances for clinical application may have certain adverse effects, so that the quality control of the citric acid maropiptan is very important.
Disclosure of Invention
Aiming at the problem that a detection method of a citric acid marziptan related substance does not exist in the prior art, the invention provides a detection method of citric acid marziptan and related substances thereof.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a detection method of maririptan citrate and related substances thereof comprises the steps of preparing a solution to be detected by using a methanol solution of 0.1-0.2% v/v triethylamine as a solvent, and measuring the related substances by using a high performance liquid chromatography, wherein the chromatographic conditions of the high performance liquid chromatography are as follows:
a chromatographic column: octadecyl bonding silica gel column;
mobile phase: the mobile phase A is 0.005-0.015 mol/L dipotassium hydrogen phosphate solution, and the pH value is adjusted to 7.30-7.70 by using phosphoric acid; the mobile phase B is acetonitrile; the mobile phase C is methanol;
performing gradient elution by using the mobile phase A, the mobile phase B and the mobile phase C, wherein the elution gradient is as follows:
the detection wavelength is 200-240 nm;
the column temperature is 38-42 ℃.
The detection method of the citric acid maropritan and related substances thereof can realize effective separation of main components and known impurities, accurately, qualitatively and quantitatively detect the citric acid maropritan and impurity conditions thereof, and is discovered through methodology researches and verifications such as specificity, sensitivity and the like.
Taking mobile phase a as an example, the elution gradient is specifically expressed as: the volume percentage of the mobile phase A is reduced from 49 to 51 percent to 25 percent at a constant speed for 0min to 7min, the volume percentage of the mobile phase A is reduced from 25 percent to 21.5 percent at a constant speed for 7min to 9min, the volume percentage of the mobile phase A is increased from 21.5 percent to 49 to 51 percent at a constant speed for 30min to 30.1min, and the volume percentage of the mobile phase A is 49 to 51 percent
Preferably, the related substances include 2-benzylidene quinuclidinone, (2S) -2-benzhydrylquinuclidinone, (2S,3S) -2-benzhydrylquinuclidinone benzylamine, (2S,3S) -2-benzhydrylquinuclidin-3-amine, 5-tert-butyl-2 methoxybenzaldehyde, and (2S,3S) -2-benzhydryl-N- (5-tert-butyl-2-methoxybenzyl) quinuclidin-3-imine. The impurities are introduced or generated by degradation in the synthesis process of the citric acid maropiptan.
Preferably, the elution gradient is as follows:
preferably, the flow rate is 1.0 ml/min.
Preferably, the detection wavelength is 222 nm.
Preferably, the column temperature is 40 ℃.
Preferably, the pH of the mobile phase a is 7.50.
Preferably, the concentration of the dipotassium hydrogen phosphate in the dipotassium hydrogen phosphate solution is 0.01 mol/L.
Preferably, the solution to be tested is prepared with 0.2% v/v triethylamine in methanol as solvent.
Preferably, the chromatographic column is CAPCELL PAK C18, with the specification: 4.6X 250mm, filler particle size 5 μm.
Preferably, the detection method comprises the steps of:
step a, preparing a test solution and a control solution with at least five concentrations of citric acid and mariopram and related substances;
b, measuring the reference solution by using the high performance liquid chromatography to obtain a linear regression equation;
and c, measuring the test solution by using the high performance liquid chromatography, and calculating the contents of the maririptan citrate and related substances in the test solution by using the linear regression equation obtained in the step b.
The invention has the beneficial effects that: the chromatographic condition specificity is high, the system is stable, the linearity is good, the precision is high, the accuracy is high, the durability test is good, and the citric acid malapidan and related substances thereof can be effectively measured.
Drawings
FIG. 1 is a chromatogram of a system suitability solution under the system suitability term in example 1;
FIG. 2 is a chromatogram of a test solution under the special attribute items in example 1;
FIG. 3 is a chromatogram of a detection limiting solution under the detection limiting amount in example 1;
FIG. 4 is a chromatogram of a limiting solution under the limit of detection in example 1.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the following examples, impurity A is 2-benzylidene quinuclidinone, impurity B is (2S) -2-benzhydrylquinuclidinone, impurity C is (2S,3S) -2-benzhydrylquinuclidinone benzylamine, impurity D is (2S,3S) -2-benzhydrylquinuclidinone-3-amine, impurity E is 5-tert-butyl-2 methoxybenzaldehyde, and impurity F is (2S,3S) -2-benzhydryl-N- (5-tert-butyl-2-methoxybenzyl) quinuclidin-3-imine.
The instrument comprises the following steps: high performance liquid chromatograph, diode array detector, measuring flask, electronic balance.
Blank solvent: 0.2% v/v triethylamine in methanol.
Example 1
The embodiment of the invention provides a detection method of maririptan citrate and related substances thereof.
1.1 preparation of the solution
Preparing an impurity stock solution: taking appropriate amount of reference substances of impurity A, impurity B, impurity C, impurity D, impurity E and impurity F respectively, precisely weighing, adding 0.2% v/v methanol solution of triethylamine respectively, dissolving and diluting to obtain 1mL of stock solution containing 0.08mg of each impurity.
Preparation of a test solution: taking a proper amount of the citric acid Maropritan test sample, adding 0.2% v/v methanol solution of triethylamine to dissolve and dilute to prepare 1mL of the test sample containing 0.4mg/mL citric acid Maropritan.
Preparing a first-grade stock solution of a reference substance: precisely measuring 2.0mL of each reference substance, placing the reference substance in a 10mL volumetric flask, dissolving the reference substance with 0.2% v/v of triethylamine methanol solution to a constant volume to a scale, and shaking up to obtain a first-stage stock solution of each reference substance.
Mixing the reference solution: accurately measuring a proper amount of a first-grade stock solution of a citric acid malopram reference substance, an impurity A, an impurity B, an impurity C, an impurity D, an impurity E and an impurity F, and diluting the stock solution with a methanol solution of 0.2% v/v triethylamine to prepare a mixed solution containing 0.8 mu g/ml of citric acid malopram, the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F.
Preparing various impurities and a citric acid maropiptan positioning solution: respectively and precisely measuring appropriate amounts of the first-grade stock solution of the hippopotamus citrate reference substance, impurity A, impurity B, impurity C, impurity D, impurity E and impurity F, and respectively diluting with 0.2% v/v of triethylamine methanol solution to prepare a positioning solution containing 0.8 mu g/ml of content of the hippopotamus citrate, impurity A, impurity B, impurity C, impurity D, impurity E and impurity F.
1.2 conditions of high performance liquid chromatography:
and (3) chromatographic column: CAPCELL PAK C18 (4.6X 250mm)5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 222 nm;
column temperature: 40 ℃;
concentration of test solution: 0.4 mg/ml;
sample introduction amount: 20 mu l of the mixture;
mobile phase a phase: 0.01mol/L dipotassium hydrogen phosphate solution (pH7.50), and the preparation method comprises the following steps: dissolving dipotassium hydrogen phosphate 2.28g in water 900ml, adjusting pH to 7.50 with phosphoric acid, adding water to 1000ml, shaking up, and filtering to obtain the final product;
mobile phase B phase: acetonitrile;
mobile phase C phase: methanol.
Elution was performed according to the following gradient program:
time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
0 | 50 | 45 | 5 |
7 | 25 | 70 | 5 |
9 | 21.5 | 73.5 | 5 |
30 | 21.5 | 73.5 | 5 |
30.1 | 50 | 45 | 5 |
50 | 50 | 45 | 5 |
1.3 methodological validation:
1. system applicability
Sampling blank solvent and mixed reference solution (i.e. system applicability solution) for detection, wherein the system applicability solution is continuously sampled for 6 needles, sampling for detection according to 1.2 high performance liquid chromatography conditions, the sampling amount is 20 μ l, and recording chromatogram as shown in figure 1. The test result data are shown in table 1.
TABLE 1 System suitability test results
As can be seen from FIG. 1, the baseline is stable and has no interference, and the blank solvent has no interference on the detection of impurities and main components; as can be seen from the data in Table 1, the RSD values of the peak areas and the retention times of the impurity A, B, C, D, E, F and the Mariotan citrate are all in accordance with the requirements, and the separation degrees of each impurity and the main peak Mariotan citrate are in accordance with the regulations and are suitable for the inspection of related substances.
The test results show that the system of the method has good applicability.
2. Specificity
And (3) respectively sampling and detecting the blank solvent, the impurity positioning solution, the test solution and the mixed reference solution according to the high performance liquid chromatography condition of 1.2, wherein the sampling amount is 20 mu l, recording a chromatogram, the chromatogram of the test solution is shown in figure 2, the test result data of the test solution is shown in table 2, and the test result data of the mixed reference solution is shown in table 3.
TABLE 2 test results of test solutions
Name(s) | Retention time (min) | Peak area | Degree of separation |
Impurity B | 8.030 | 9787 | - |
Impurity C | 13.940 | 26386 | 13.267 |
Impurity E | 10.392 | 2160 | 11.265 |
Maropritan citrate | 25.637 | 17523974 | 23.889 |
The impurity A, D, F was not detected in the test sample.
TABLE 3 test results of the mixed control solutions
Test results show that the minimum separation degrees between impurity peaks and between each impurity peak and the Maropritan citrate are all larger than 1.5, and no interference exists between impurities and between each impurity and the Maropritan citrate, so that the method has good specificity.
3. Detection limit and quantification limit
Taking each impurity stock solution and a reference substance primary stock solution of the citric acid malapidium, and respectively measuring the quantitative limit (S/N is more than or equal to 10) and the detection limit (S/N is more than or equal to 3) by a dilution method, wherein the chromatogram of the detection limit solution is shown in figure 3, and the chromatogram of the quantitative limit solution is shown in figure 4. The test results are shown in Table 4.
TABLE 4 detection limit and quantitation limit test results
Sample (I) | Quantitative limit concentration (mug/mL) | Detection limit concentration (mug/mL) |
Impurity A | 0.096 | 0.032 |
Impurity B | 0.100 | 0.033 |
Impurity C | 0.185 | 0.061 |
Impurity D | 0.160 | 0.053 |
Impurity E | 0.040 | 0.013 |
Impurity F | 0.295 | 0.097 |
Marupitan | 0.320 | 0.106 |
The test result shows that the detection limit concentrations of the impurity A, B, C, D, E, F and the hippopotamus citrate are respectively 0.096 mu g/mL, 0.100 mu g/mL, 0.185 mu g/mL, 0.160 mu g/mL, 0.040 mu g/mL, 0.295 mu g/mL and 0.320 mu g/mL; the concentrations of the quantitative limits were 0.032. mu.g/mL, 0.033. mu.g/mL, 0.061. mu.g/mL, 0.053. mu.g/mL, 0.013. mu.g/mL, 0.097. mu.g/mL, and 0.106. mu.g/mL, respectively. The test results show that the method has high sensitivity.
4. Linear range
Precisely weighing appropriate amounts of impurity A, impurity B, impurity C, impurity D, impurity E and impurity F, respectively dissolving and diluting with blank solvent to obtain a series of concentration solutions with concentrations of 1.60 μ g/mL, 1.20 μ g/mL, 0.96 μ g/mL, 0.80 μ g/mL, 0.64 μ g/mL and 0.40 μ g/mL.
An appropriate amount of the citric acid Marupitan reference substance is precisely weighed, and is respectively dissolved and diluted by a blank solvent to prepare a series of concentration solutions with the concentrations of 2.320 mu g/mL, 1.740 mu g/mL, 1.392 mu g/mL, 1.160 mu g/mL, 0.928 mu g/mL and 0.580 mu g/mL.
Precisely measuring 20 μ L of each reference solution, injecting into high performance liquid chromatograph, detecting according to 1.2 high performance liquid chromatography conditions, recording chromatogram, measuring peak area, and performing linear regression with peak area A as ordinate and concentration C as abscissa, the results are shown in Table 5.
TABLE 5 Linear results
Sample(s) | Linear equation of equations | R2 | Linear Range (μ g/ml) |
Impurity A | y=40569x+880.95 | 0.9997 | 0.40~1.60 |
Impurity B | y=38108x+431.93 | 0.9999 | 0.40~1.60 |
Impurity C | y=36102x+32.493 | 0.9996 | 0.40~1.60 |
Impurity D | y=25049x-122.54 | 0.9992 | 0.40~1.60 |
Impurity E | y=102379x+3325.8 | 0.9998 | 0.40~1.60 |
Impurity F | y=57808x-2403.4 | 0.9996 | 0.40~1.60 |
Maropritan citrate | y=33020x+1381 | 0.9995 | 0.58~2.32 |
The above results show that the concentration of the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F in the range of 0.40 to 1.60 mu g/ml R2Respectively 0.9997, 0.9999, 0.9996, 0.9992, 0.9998 and 0.9996, and the concentration of the citric acid of the20.9995, indicating that the method has a good linear relationship between concentration and peak area.
5. Accuracy of
50% test solution: weighing 29mg of citric acid malopiptan and 0.2% v/v triethylamine methanol solution for dissolving, respectively taking appropriate amount of reference substance primary stock solution of impurities A, B, C, D, E and F, and adding 0.2% v/v triethylamine methanol solution to prepare solution containing 0.4 mug/mL of each of the impurities A, B, C, D, E and F and 0.4mg/mL of citric acid malopiptan, thus obtaining the product.
100% test solution: weighing 29mg of malupitan citrate, adding a diluent, dissolving, respectively taking a proper amount of a reference substance primary stock solution of the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F, and adding 0.2% v/v of triethylamine methanol solution to prepare a solution containing 0.8 mu g/mL of each of the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F and 0.4mg/mL of malupitan citrate, thus obtaining the product.
150% test solution: weighing 29mg of malupitan citrate, adding a diluent, dissolving, respectively taking a proper amount of a reference substance primary stock solution of the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F, and adding 0.2% v/v of triethylamine methanol solution to prepare a solution containing 1.2 mu g/mL of each of the impurity A, the impurity B, the impurity C, the impurity D, the impurity E and the impurity F and 0.4mg/mL of malupitan citrate, thus obtaining the product.
Three samples were prepared in parallel for each concentration and tested as described above.
Precisely measuring the solutions to obtain 20 μ L, injecting into a liquid chromatograph, detecting by sample injection under high performance liquid chromatography condition of 1.2, and recording chromatogram, wherein the result is shown in Table 6 below.
TABLE 6 recovery test results
The results show that the recovery rate of each impurity at each concentration is within the range of 92-105%, and the RSD value is less than 2%, which indicates that the method has good accuracy.
Example 2
The embodiment provides a detection method of maririptan citrate and related substances thereof, and conditions of high performance liquid chromatography are as follows:
and (3) chromatographic column: CAPCELL PAK C18 (4.6X 250mm)5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 222 nm;
column temperature, 38 ℃;
concentration of the test solution: 0.4 mg/ml;
sample injection amount: 20 mu l of the mixture;
mobile phase a phase: 0.01mol/L dipotassium hydrogenphosphate solution (pH7.50) prepared by the same method as in example 1;
mobile phase B phase: acetonitrile;
mobile phase C phase: methanol.
Gradient program conditions were the same as in example 1.
The blank solvent, the mixed control solution of example 1, and the sample solution were measured precisely at 20. mu.L each, and the solutions were injected into a liquid chromatograph, measured by the high performance liquid chromatography, and the peak areas of the components were recorded to record the chromatogram, and the results are shown in tables 7 and 8.
TABLE 7 test results of the mixed control solution
Mixed control solution | Retention time min | Degree of separation |
Impurity A | 9.319 | 6.149 |
Impurity B | 8.131 | 18.37 |
Impurity C | 13.853 | 12.394 |
Impurity D | 4.614 | - |
Impurity E | 10.56 | 6.076 |
Impurity F | 28.97 | 4.346 |
Maropritan citrate | 25.811 | 23.338 |
TABLE 8 test results of substances related to the test solutions
Test solution | Retention time min | Degree of separation |
Impurity B | 8.128 | — |
Impurity C | 13.862 | 11.610 |
Impurity E | 10.576 | 11.146 |
Maropritan citrate | 25.778 | 23.412 |
Example 3
The embodiment provides a detection method of maririptan citrate and related substances thereof, and conditions of high performance liquid chromatography are as follows:
a chromatographic column: CAPCELL PAK C18 (4.6X 250mm)5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 222 nm;
column temperature, 42 ℃;
concentration of the test solution: 0.4 mg/ml;
sample introduction amount: 20 mu l of the solution;
mobile phase a phase: 0.01mol/L dipotassium hydrogenphosphate solution (pH7.50) prepared by the same method as in example 1;
mobile phase B phase: acetonitrile;
mobile phase C phase: methanol.
Gradient elution conditions were the same as in example 1.
The blank solvent, the mixed control solution of example 1 and the sample solution were measured precisely at 20. mu.L each, and the solutions were injected into a liquid chromatograph, and the samples were injected and measured under the conditions of the high performance liquid chromatography, and the peak areas of the components were recorded to record the chromatogram, and the results are shown in tables 9 and 10.
TABLE 9 test results of the mixed control solution
Mixed control solution | Retention time min | Degree of separation |
Impurity A | 9.163 | 5.089 |
Impurity B | 8.064 | 14.889 |
Impurity C | 13.965 | 12.087 |
Impurity D | 4.803 | — |
Impurity E | 10.367 | 5.245 |
Impurity F | 28.432 | 3.846 |
Maropritan citrate | 25.543 | 21.273 |
TABLE 10 test results of substances related to the test solutions
Test solution | Retention time min | Degree of separation |
Impurity B | 8.050 | — |
Impurity C | 13.962 | 11.064 |
Impurity E | 10.370 | 8.499 |
Maropritan citrate | 25.505 | 20.177 |
Example 4
The embodiment provides a detection method of maririptan citrate and related substances thereof, and conditions of high performance liquid chromatography are as follows:
a chromatographic column: CAPCELL PAK C18 (4.6X 250mm)5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 222 nm;
column temperature, 40 ℃;
concentration of test solution: 0.4 mg/ml;
sample introduction amount: 20 mu l of the solution;
mobile phase a phase: 0.01mol/L dipotassium hydrogenphosphate solution (pH7.50) prepared by the same method as in example 1;
mobile phase B phase: the reaction mixture of acetonitrile and water is mixed,
mobile phase C phase: methanol.
Elution was performed according to the following gradient program:
time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
0 | 49 | 46 | 5 |
7 | 25 | 70 | 5 |
9 | 21.5 | 73.5 | 5 |
30 | 21.5 | 73.5 | 5 |
30.1 | 49 | 46 | 5 |
50 | 49 | 46 | 5 |
The blank solvent, the mixed control solution of example 1, and the sample solution were measured precisely at 20. mu.L each, and the solutions were injected into a liquid chromatograph, and the sample was measured under the conditions of the above high performance liquid chromatography, and the peak areas of the respective components were recorded to record chromatograms, and the results are shown in tables 11 and 12.
TABLE 11 test results of mixed control solutions
TABLE 12 test results of substances related to the test solutions
Test solution | Retention time min | Degree of separation |
Impurity B | 7.963 | - |
Impurity C | 13.792 | 15.008 |
Impurity E | 10.417 | 12.717 |
Maropritan citrate | 25.689 | 28.585 |
Example 5
The embodiment provides a detection method of maririptan citrate and related substances thereof, and conditions of high performance liquid chromatography are as follows:
a chromatographic column: CAPCELL PAK C18 (4.6X 250mm)5 μm;
flow rate: 1.0 ml/min;
detection wavelength: 222 nm;
column temperature, 40 ℃;
concentration of the test solution: 0.4 mg/ml;
sample introduction amount: 20 mu l of the mixture;
mobile phase a phase: 0.01mol/L dipotassium hydrogenphosphate solution (pH7.50) prepared by the same method as in example 1;
mobile phase B phase: acetonitrile;
mobile phase C phase: methanol.
Elution was performed according to the following gradient program:
time (min) | Mobile phase A (%) | Mobile phase B (%) | Mobile phase C (%) |
0 | 51 | 44 | 5 |
7 | 25 | 70 | 5 |
9 | 21.5 | 73.5 | 5 |
30 | 21.5 | 73.5 | 5 |
30.1 | 51 | 44 | 5 |
50 | 51 | 44 | 5 |
The blank solvent, the mixed control solution of example 1, and the sample solution were measured precisely at 20. mu.L each, and the solutions were injected into a liquid chromatograph, and the sample was measured under the conditions of the above high performance liquid chromatography, and the peak areas of the respective components were recorded to record chromatograms, and the results are shown in tables 13 and 14.
TABLE 13 test results of the mixed control solution
Mixed control solution | Retention time min | Degree of separation |
Impurity A | 9.369 | 6.672 |
Impurity B | 8.240 | 21.676 |
Impurity C | 13.957 | 14.791 |
Impurity D | 4.621 | - |
Impurity E | 10.593 | 6.998 |
Impurity F | 29.008 | 5.101 |
Maropritan citrate | 25.881 | 27.830 |
TABLE 14 test results of substances related to the test solutions
Test solution | Retention time min | Degree of separation |
Impurity B | 8.193 | — |
Impurity C | 13.953 | 15.058 |
Impurity E | 10.584 | 12.587 |
Maropritan citrate | 25.836 | 28.439 |
The above description is intended to be illustrative of the preferred embodiment of the present invention and should not be taken as limiting the invention, but rather, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.
Claims (8)
1. A detection method of maririptan citrate and related substances thereof is characterized in that a methanol solution of 0.1-0.2% v/v triethylamine is used as a solvent to prepare a solution to be detected, and a high performance liquid chromatography is used for detecting the related substances, wherein the chromatographic conditions of the high performance liquid chromatography are as follows:
and (3) chromatographic column: octadecyl bonding silica gel column;
mobile phase: the mobile phase A is 0.005-0.015 mol/L dipotassium hydrogen phosphate solution, and the pH value is adjusted to 7.30-7.70 by using phosphoric acid; the mobile phase B is acetonitrile; the mobile phase C is methanol;
and (3) carrying out gradient elution by adopting the mobile phase A, the mobile phase B and the mobile phase C, wherein the elution gradient is as follows:
the detection wavelength is 200-240 nm;
the column temperature is 38-42 ℃;
the related substances include 2-benzylidene quinuclidinone, (2S) -2-benzhydryl quinuclidinone, (2S,3S) -2-benzhydryl quinuclidinone benzylamine, (2S,3S) -2-benzhydryl quinuclidinone-3-amine, 5-tert-butyl-2 methoxybenzaldehyde and (2S,3S) -2-benzhydryl-N- (5-tert-butyl-2-methoxybenzyl) quinuclidin-3-imine.
3. the method for detecting maririptan citrate and related substances according to claim 1, wherein the flow rate is 1.0 ml/min; and/or
The detection wavelength is 222 nm; and/or
The column temperature was 40 ℃.
4. The method for detecting maririptan citrate and related substances according to claim 1, wherein the pH value of the mobile phase A is 7.50.
5. The method for detecting maririptan citrate and related substances according to claim 1, wherein the concentration of dipotassium hydrogen phosphate in the dipotassium hydrogen phosphate solution is 0.01 mol/L.
6. The method for detecting maririptan citrate and related substances according to claim 1, wherein a methanol solution of 0.2% v/v triethylamine is used as a solvent to prepare a solution to be detected.
7. The method for detecting maririptan citrate and related substances according to claim 1, wherein the chromatographic column is CAPCELL PAK C18, and the specification is as follows: 4.6X 250mm, filler particle size 5 μm.
8. The detection method of maririptan citrate and related substances according to any one of claims 1 to 7, characterized by comprising the following steps:
step a, preparing a test solution and at least five concentrations of control solutions of the citric acid maropiptan and related substances thereof;
b, measuring the reference substance solution by using the high performance liquid chromatography to obtain a linear regression equation;
and c, measuring the test solution by using the high performance liquid chromatography, and calculating the contents of the maririptan citrate and related substances in the test solution by using the linear regression equation obtained in the step b.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011424925.0A CN112557541B (en) | 2020-12-08 | 2020-12-08 | Detection method of maropiptan citrate and related substances thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011424925.0A CN112557541B (en) | 2020-12-08 | 2020-12-08 | Detection method of maropiptan citrate and related substances thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112557541A CN112557541A (en) | 2021-03-26 |
CN112557541B true CN112557541B (en) | 2022-07-12 |
Family
ID=75059829
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011424925.0A Active CN112557541B (en) | 2020-12-08 | 2020-12-08 | Detection method of maropiptan citrate and related substances thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112557541B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105308052A (en) * | 2013-04-18 | 2016-02-03 | Q生物有限公司 | Methods and compositions for wound healing |
EP3022231A1 (en) * | 2013-07-17 | 2016-05-25 | Curadev Pharma Pvt. Ltd. | Cyclodextrin |
CN105997703A (en) * | 2016-07-05 | 2016-10-12 | 上海相宜本草化妆品股份有限公司 | Olive leaf extract and cosmetics containing same |
CN108341811A (en) * | 2017-01-23 | 2018-07-31 | 科贝源(北京)生物医药科技有限公司 | The preparation method of Ma Luopitan impurity |
CN110398541A (en) * | 2018-04-24 | 2019-11-01 | 广东东阳光药业有限公司 | A method of citric acid horse sieve is smooth and its optical isomer for separation and measurement |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011089215A1 (en) * | 2010-01-22 | 2011-07-28 | Ascendis Pharma As | Dipeptide-based prodrug linkers for aromatic amine-containing drugs |
-
2020
- 2020-12-08 CN CN202011424925.0A patent/CN112557541B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105308052A (en) * | 2013-04-18 | 2016-02-03 | Q生物有限公司 | Methods and compositions for wound healing |
EP3022231A1 (en) * | 2013-07-17 | 2016-05-25 | Curadev Pharma Pvt. Ltd. | Cyclodextrin |
CN105997703A (en) * | 2016-07-05 | 2016-10-12 | 上海相宜本草化妆品股份有限公司 | Olive leaf extract and cosmetics containing same |
CN108341811A (en) * | 2017-01-23 | 2018-07-31 | 科贝源(北京)生物医药科技有限公司 | The preparation method of Ma Luopitan impurity |
CN110398541A (en) * | 2018-04-24 | 2019-11-01 | 广东东阳光药业有限公司 | A method of citric acid horse sieve is smooth and its optical isomer for separation and measurement |
Non-Patent Citations (3)
Title |
---|
Pharmacokinetics of single doses of maropitant citrate in adult horses;Emily H. Berryhill 等;《JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS》;20190731;第42卷(第4期);第487-491页 * |
Process Research and Development of an NK-1 Receptor Antagonist.Enantioselective Trifluoromethyl Addition to a Ketone in the Preparation of a Chiral Isochroman;Stéphane Caron DENG;《Organic Process Research & Development》;20071231;第11卷;第1015-1024页 * |
分子排阻色谱法测定马罗匹坦注射液中磺丁倍他环糊精钠的含量;于晓辉 等;《安徽农业科》;20151231;第43卷(第21期);第154-156页 * |
Also Published As
Publication number | Publication date |
---|---|
CN112557541A (en) | 2021-03-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN115060832A (en) | Method for detecting contents of oxcarbazepine and preservative in oxcarbazepine oral suspension | |
CN111122736B (en) | Method for detecting enantiomer in intermediate of brivaracetam | |
CN112611820A (en) | Method for measuring residual solvent of ozagrel sodium | |
CN112557541B (en) | Detection method of maropiptan citrate and related substances thereof | |
CN115097023B (en) | High performance liquid chromatography detection method for zomib amine related substances | |
CN113514588B (en) | High performance liquid chromatography analysis method of relevant substances of cysteamine for injection | |
CN115616133A (en) | Method for detecting cysteine in compound amino acid injection and application thereof | |
CN113030328B (en) | Method for detecting genotoxic impurities in ivabradine hydrochloride | |
CN111505163B (en) | Method for detecting phenethyl methane sulfonate substances | |
CN114518413A (en) | Method for measuring content of proline in captopril raw material medicine | |
CN114200050B (en) | HPLC detection method for content of related substances in p-bromoanisole | |
CN114113402B (en) | Method for measuring pinanediol content in bortezomib by adopting high performance liquid chromatography | |
CN113125585B (en) | Method for detecting R-4-propyl-dihydrofuran-2-ketone or/and related substances thereof | |
CN115453014B (en) | Detection method of butylphthalide and related substances thereof | |
CN113125586B (en) | Detection method of 1- [2- (2, 4-dimethyl-thiophenyl) -phenyl ] piperazine and isomer thereof | |
CN115469039B (en) | Butylphthalide and detection method of related substances thereof | |
CN116930368B (en) | Detection method of settop alcohol isomer | |
CN113514589B (en) | High performance liquid chromatography analysis method of stannous glucoheptonate relative substance for injection | |
CN112034058B (en) | Method for detecting isomer impurities in vincamine | |
CN117630202A (en) | Method for detecting buspirone hydrochloride intermediate impurities | |
CN117741025A (en) | Method for detecting impurities in ethyl 2,3-dibromopropionate | |
CN111257440A (en) | GC-HS-based method for determining potential genotoxic impurities in sodium valproate | |
CN117871737A (en) | Detection method of adenosine injection | |
CN118050445A (en) | Method for detecting glycerol parahydroxybenzoate in levetiracetam oral liquid | |
CN114324673A (en) | Analysis method for simultaneously determining chloromalastine fumarate and isomers thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |