CN111505154A - Detection method for mosapride citrate and five key impurities in preparation thereof - Google Patents
Detection method for mosapride citrate and five key impurities in preparation thereof Download PDFInfo
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- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960004085 mosapride Drugs 0.000 title claims abstract description 70
- 239000012535 impurity Substances 0.000 title claims abstract description 34
- 238000001514 detection method Methods 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 40
- 239000000126 substance Substances 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 10
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 51
- 239000000243 solution Substances 0.000 claims description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000011259 mixed solution Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000337 buffer salt Substances 0.000 claims description 5
- 238000009642 citrate test Methods 0.000 claims description 5
- 238000010829 isocratic elution Methods 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 3
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
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- 239000008187 granular material Substances 0.000 claims 1
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- 239000012085 test solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000000227 grinding Methods 0.000 description 6
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- 230000015572 biosynthetic process Effects 0.000 description 5
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
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- 239000007924 injection Substances 0.000 description 4
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- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
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- 238000012494 forced degradation Methods 0.000 description 3
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- 239000002994 raw material Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- 108091005482 5-HT4 receptors Proteins 0.000 description 1
- 235000007627 Caesalpinia Nutrition 0.000 description 1
- 241000522234 Caesalpinia Species 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 1
- UCSNADLUTDWSLM-UHFFFAOYSA-N N-[[4-[(4-fluorophenyl)methyl]morpholin-2-yl]methyl]benzamide 2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(F)=CC=C1CN1CC(CNC(=O)C=2C=CC=CC=2)OCC1 UCSNADLUTDWSLM-UHFFFAOYSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006115 defluorination reaction Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- 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
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- 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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- 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
- G01N30/8675—Evaluation, i.e. decoding of the signal into analytical information
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- General Health & Medical Sciences (AREA)
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Abstract
A method for detecting five key impurities in mosapride citrate and a preparation thereof. The invention belongs to the technical field of medicine quality detection methods, and particularly relates to a method for detecting 5 key impurities in mosapride citrate and a preparation thereof by adopting a high performance liquid chromatography. The method has the advantages of good separation degree of related substances, high sensitivity, simple and convenient operation, stable baseline and short analysis time.
Description
Technical Field
The invention relates to the field of drug detection, in particular to a method for detecting related substances of mosapride citrate.
Technical Field
The mosapride citrate is a strong and selective 5-HT4 receptor agonist, stimulates the release of acetylcholine, enhances the movement of stomach and duodenum, and is a novel, safe and effective digestive tract dynamic drug. Mosapride citrate tablets (trade name: Gaussun) were developed by Sumitomo pharmaceutical Co., Ltd, and were first marketed in Japan in 10 months of 1998. Chemical name of Chinese 4-amino-5-chloro-2-ethoxy-N- { [4- (4-fluorobenzyl) -2-morpholinyl]Methyl benzamide citrate; the molecular formula is as follows: c21H25ClFN3O3·C6H8O7·2H2O, molecular weight: 650.05, having the formula:
the synthesis route of the mosapride citrate bulk drug is as follows. In the synthesis process, process impurities are introduced from the aspects of starting materials, side reactions and the like, and degradation impurities are generated in the storage process due to the influence of environmental factors such as oxidation and the like. The presence of these impurities not only affects the quality of the product, but also poses a major risk in terms of safety of the drug administration, and therefore it is necessary to control the presence of these impurities.
According to the analysis of the structure of the mosapride citrate and the combination of the information of related products of the mosapride citrate of the Nippon Sumitomo pharmaceutical Co., Ltd, the main process impurities and degradation impurities in the mosapride citrate can be determined as follows:
impurity A is an intermediate for synthesizing mosapride and is also a degradation product, the degradation path is generated by hydrolyzing mosapride, and the reaction formula is as follows:
the impurity B is a defluorinated product of the mosapride and is a byproduct generated in the synthesis process of the bulk drug mosapride. In the synthesis process of mosapride, starting materials p-fluorobenzaldehyde and ethanolamine are subjected to reductive amination to prepare an intermediate 1, and NaBH is subjected to reaction4And (3) reducing and removing fluorine atoms on a benzene ring under reducing conditions to obtain a byproduct 1. The byproduct 1 and the intermediate 1 have similar structures and similar polarities, are not easy to completely remove during separation and purification, remain in the intermediate 1, and participate in the next three-step reaction until the defluorination byproduct impurity B of the mosapride is generated.
The route of formation of impurity B is as follows:
impurity C is a degradation product of mosapride, and is generated under the conditions of heating, illumination or acidity by the following routes:
the impurity D is a condensation product of mosapride and citric acid, and is generated under the heating condition by the following steps:
impurity E is an oxidation product of mosapride, and is generated under illumination or oxidation conditions by the following route:
the analysis methods adopted in the literatures of Wangkong mountain HP L C on mosapride citrate tablet (Chin J Pharm Anal 2011, 31(12)), Chen Steel and the like, HP L C on mosapride citrate capsule (Chin JMAP,2010September, Vol.27No.9), Sun Ling and the like, HP L C on mosapride hydrochloride capsule (Chinese Journal of Pharmaceuticals2004,35(6)) and the like, only the raw material medicines are subjected to forced degradation experiments, and the impurities A-E are detected by adopting the methods, so that the effective separation can not be realized.
In addition, the impurity detection is carried out by adopting a gradient elution method in the methods (Z L201410312949.5) for detecting the related substances of the mosapride citrate, which are shown in Japanese pharmacopoeia standard of the mosapride citrate, Liuwenhua and the like, and in the method (Z L201410312949.5) for detecting the related substances of the mosapride citrate, which is shown in the patent of Caesalpinia and the like.
Therefore, an analysis method which can effectively separate various impurities and has the advantages of simple operation, small interference and short analysis time is sought, and the method has important significance for controlling related substances in the mosapride citrate and related products thereof.
Disclosure of Invention
In order to solve the technical problems, the invention provides a detection method of mosapride citrate related substances, which has stable baseline, short analysis time and high reproducibility, can effectively separate various impurities and comprises the following steps:
dissolving the mosapride citrate test sample in methanol, diluting the solution to a solution containing about 1mg per 1ml, and filtering to obtain a subsequent filtrate as a solution to be detected.
Taking a solution to be detected, and detecting by using a high performance liquid chromatography, wherein the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; the mixed solution of the buffer salt solution and the organic solvent is taken as a mobile phase, isocratic elution is adopted, the column temperature is 30-40 ℃, the flow rate is 0.8-1.2 ml/min, and the detection wavelength is 274 nm.
The invention provides a method for detecting related substances of mosapride citrate, wherein in the chromatographic condition, a buffer salt solution is a citric acid solution.
The method for detecting the mosapride citrate related substances, provided by the invention, comprises the step of detecting a citric acid solution by using a chromatographic condition, wherein the concentration of the citric acid solution is 30-60 mmol/ml, preferably 40-50 mmol/L, and further preferably 50 mmol/L.
The detection method of mosapride citrate related substances, provided by the invention, comprises the step of taking a buffer salt solution as a citric acid solution under the chromatographic condition, wherein the pH value of the citric acid solution is 3.5-4.5, preferably 3.8-42, and further preferably 4.0. The pH regulator is phosphoric acid and sodium hydroxide solution, and the pH regulator is preferably sodium hydroxide solution.
The invention provides a detection method of mosapride citrate related substances, wherein in the chromatographic condition, an organic solvent mixture is a mixed solution of methanol and acetonitrile, and the volume ratio of the methanol to the acetonitrile is 30-40: 15-5, preferably 35: 10.
The invention provides a detection method of mosapride citrate related substances, wherein in the chromatographic condition, the volume ratio of citric acid buffer salt to a mixture of methanol and acetonitrile is 50-60: 50-40, and preferably 55: 45.
The invention provides a method for detecting related substances of mosapride citrate, wherein in the chromatographic condition, the column temperature is 30-45 ℃, the flow rate is 0.8-1.2 ml/min, preferably the column temperature is 40 ℃, and the flow rate is 1 ml/min.
The invention further provides a detection method of mosapride citrate related substances, which comprises the following steps:
(a) preparation of system suitability solution: weighing 10mg of related substances A-E of the mosapride citrate respectively, putting the related substances into 5 measuring bottles with the volume of 20ml, adding methanol to dissolve and dilute the related substances to the scale, and shaking up; and putting 1ml of the solution into a 100ml measuring flask respectively, adding 10mmg of mosapride citrate, adding methanol to dissolve and dilute the solution to a scale, and shaking up the solution to obtain the compound. (containing mosapride citrate 1mg/ml, each impurity 5. mu.g/ml)
(b) Preparation of a test solution: taking a proper amount of mosapride citrate test sample, grinding, weighing a proper amount of fine powder (about 10mg equivalent to mosapride citrate), precisely weighing, adding methanol to dissolve and dilute into 1ml of solution containing about 1mg, filtering, and taking a subsequent filtrate to obtain the mosapride citrate test sample.
(c) Chromatographic conditions are as follows: the chromatographic column takes octadecylsilane chemically bonded silica as a filler; isocratic elution is adopted, and the mobile phase is citric acid solution: methanol: acetonitrile (55:35:10), column temperature 40 ℃, flow rate 1ml/min, detection wavelength 274nm, sample volume 10. mu.l.
Wherein, in the mobile phase, the components are in volume ratio; the citric acid solution was adjusted to pH 4.0 with sodium hydroxide solution.
(d) And (3) determination: sucking the system applicability solution and the sample solution, injecting into a liquid chromatograph, and measuring by high performance liquid chromatography.
The inventor of the application examines the influence of the mobile phase composition on the detection result in the detection of related substances of the mosapride citrate in detail, when the mobile phase is a mixed solution of 50 mmol/L citric acid/acetonitrile with a volume ratio of 65:35, isocratic elution is adopted, a base line is good, the separation degree of a main peak and impurities is good, but when the mobile phase is used, the impurity C is not retained and is eluted together with a solvent peak, and the accurate quantification cannot be realized.
Compared with the prior art, the method for detecting the mosapride citrate related substances has the following advantages;
1. the method for detecting the mosapride citrate related substances has good separation degree, can detect more impurities and can more effectively control the related substances in a test sample;
2. compared with the prior art, the method for detecting the mosapride citrate related substances has the advantages of more stable baseline and small background interference;
3. compared with the prior art, the method for detecting the related substances of the mosapride citrate adopts isocratic elution, is simple and convenient to operate, has better adaptability to instruments, and is easier to reproduce and popularize;
drawings
FIG. 1 is a high performance liquid chromatogram of example 1;
FIG. 2 is a high performance liquid chromatogram of example 2;
FIG. 3 is a high performance liquid chromatogram of example 3;
FIG. 4 is a high performance liquid chromatogram of a thermally disrupted sample of example 4;
FIG. 5 is a high performance liquid chromatogram of an acid-disrupted sample of example 4;
FIG. 6 is a high performance liquid chromatogram of a base-destroyed sample of example 4;
FIG. 7 is a high performance liquid chromatogram of an oxidative destruction sample of example 4;
FIG. 8 is a high performance liquid chromatogram of an illumination-damaged sample in example 4;
FIG. 9 is a high performance liquid chromatogram under high temperature conditions of example 5;
FIG. 10 is a high performance liquid chromatogram under high humidity conditions of example 5;
FIG. 11 is a high performance liquid chromatogram under light conditions of example 5.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
In the following embodiments, the drugs, reagents and instruments used are as follows:
mosapride citrate (batch: 520170104, manufacturer: Shandong New time pharmaceutical Co., Ltd.), Mosapride citrate-related substance A (T L C, batch: 0004-.
A related substance A:
the related substance B:
the related substance C:
a related substance D:
a related substance E:
example 1 screening of high Performance liquid chromatography conditions
System applicability solution preparation: weighing 10mg of related substances A-E of the mosapride citrate respectively, putting the related substances into 5 measuring bottles with the volume of 20ml, adding methanol to dissolve and dilute the related substances to the scale, and shaking up; and putting 1ml of the solution into a 100ml measuring flask respectively, adding 10mmg of mosapride citrate, adding methanol to dissolve and dilute the solution to a scale, and shaking up the solution to obtain the compound. (containing 1mg/ml of mosapride citrate and 5. mu.g/ml of each impurity).
The conditions of high performance liquid chromatography are that the mobile phase is 50 mmol/L citric acid solution (pH is adjusted to 4.0 by sodium hydroxide solution) -acetonitrile (65:35), the flow rate is 1ml/min, the detection wavelength is 274nm, the column temperature is 40 ℃, and the injection volume is 10 mul.
The sample of the system applicability solution is taken for detection, and the result is shown in figure 1, wherein the impurity B and the impurity E cannot be separated.
Example 2 screening of high Performance liquid chromatography conditions
The HPLC conditions were 50 mmol/L citric acid solution (pH adjusted to 4.0 with sodium hydroxide solution) -methanol-acetonitrile (55:35:10) as mobile phase at a flow rate of 1ml/min, detection wavelength of 274nm, column temperature of 40 deg.C, and injection volume of 10. mu.l.
The method of example 1 was used to prepare a system-applicable solution, and the results of sample injection and detection are shown in fig. 2, where known impurities were detected, the baseline was stable, and the separation of impurities from the main peak and impurities was good.
Example 3 Baseline comparison of the present method with the gradient elution method
(1) Gradient elution method (japanese pharmacopoeia method):
the high performance liquid chromatography conditions comprise that a mobile phase A is 0.03 mol/L sodium citrate buffer solution (prepared by taking 8.82g of trisodium citrate dihydrate, dissolving in 800ml of water, adjusting the pH value to 4.0 by using dilute hydrochloric acid, and adding water to dilute to 1000 ml), a mobile phase B is acetonitrile, the column temperature is 40 ℃, the flow rate is 1ml/min, the detection wavelength is 274nm, and gradient elution is carried out according to the following table.
(2) The patented method
Conditions for high performance liquid chromatography include mobile phase 50 mmol/L citric acid solution (pH adjusted to 4.0 with sodium hydroxide solution) -methanol-acetonitrile (55:35:10), column temperature 40 deg.C, flow rate 1ml/min, and detection wavelength 274 nm.
A blank solution was prepared and subjected to sample injection detection in the same manner as in example 1, and the results are shown in FIG. 3. in the gradient method of the Japanese pharmacopoeia, the fluctuation of the base line is large, and the detection of impurities in the sample may be disturbed.
Example 4 forced degradation experiments of mosapride citrate formulations
Preparation of a test solution: the mosapride citrate preparation is taken and is forcedly degraded according to the following methods respectively:
(1) thermal destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into water 5ml for dispersing, placing in water bath (95 deg.C), taking out, cooling, diluting with methanol to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(2) Acid breaking, grinding the preparation, adding a proper amount of fine powder (containing about 10mg of mosapride citrate), adding 5ml of hydrochloric acid solution to disperse, shaking, standing at room temperature, adding 5 mol/L sodium hydroxide to neutralize, adding methanol to dilute to 10ml, shaking for 20 minutes, centrifuging, and taking supernatant as test solution.
(3) Alkali destruction is prepared by grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg), adding sodium hydroxide solution 5ml for dispersion, shaking, standing at room temperature, neutralizing with 5 mol/L hydrochloric acid, adding methanol to dilute to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(4) And (3) oxidative destruction: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into hydrogen peroxide solution 5ml for dispersion, shaking, standing at room temperature, adding methanol to dilute to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
(5) And (3) light damage: grinding the preparation, adding appropriate amount of fine powder (containing mosapride citrate 10mg) into water 5ml for dispersing, shaking, standing under strong light, adding methanol to dilute to 10ml, shaking for 20 min, centrifuging, and collecting supernatant as test solution.
The solutions were separately sampled and measured under the same conditions as in example 2. The results of thermal destruction of the samples are shown in FIG. 4, the results of acid destruction of the samples are shown in FIG. 5, the results of alkali destruction of the samples are shown in FIG. 6, the results of oxidative destruction of the samples are shown in FIG. 7, and the results of light destruction of the samples are shown in FIG. 8. The result shows that the mosapride citrate sample mainly degrades the impurity A under the heating condition, mainly degrades the impurity E under the oxidizing condition, degrades the impurity A, C, E under the illumination condition, and is stable under the acid and alkali conditions. Impurities generated under each forced degradation can be effectively separated from the main peak.
Example 5 detection of Mosapride citrate drug substance samples
A sample of mosapride citrate raw material medicine is placed under the conditions of high temperature (60 ℃), high humidity (RH 92.5%) and illumination (4500L x) for 30 days, the mosapride citrate raw material medicine is prepared into a test sample according to the condition in the example 1, the test is carried out according to the condition in the example 2, the result under the high temperature condition is shown in a figure 9, the result under the high humidity condition is shown in a figure 10, the result under the illumination condition is shown in a figure 11.
Claims (10)
1. A method for detecting five key impurities in mosapride citrate and a preparation thereof is characterized by comprising the following steps: taking a mosapride citrate test sample, preparing a solution to be detected, adopting a high performance liquid chromatography, taking octadecylsilane chemically bonded silica as a filler, taking a mixture of a buffer salt solution and an organic solvent as a mobile phase, controlling the column temperature to be 30-45 ℃, the flow rate to be 0.8-1.2 ml/min and the detection wavelength to be 274 nm; the mobile phase adopts an isocratic elution mode; the 5 key impurities are related substances A-E of mosapride citrate, and the structure of the impurities is as follows:
a related substance A:
the related substance B:
the related substance C:
a related substance D:
a related substance E:
2. the method of claim 1, wherein the buffered salt solution is a citric acid solution; the concentration of the citric acid solution is 30-60 mmol/ml, and the pH is adjusted to 3.5-4.5.
3. The method of claim 1, wherein the column temperature is 40 ℃ and the flow rate is 1.0 ml/min.
4. The method according to claim 1, wherein the organic solvent mixture is a mixed solution of methanol and acetonitrile.
5. The method of claim 1, wherein the mosapride citrate test sample comprises a mosapride citrate bulk drug, a mosapride citrate granule, a mosapride citrate tablet and an intermediate.
6. The method of claim 2, wherein the pH adjustment is performed using phosphoric acid or sodium hydroxide solution.
7. The method according to claim 4, wherein the volume ratio of methanol to acetonitrile in the mixed solution of methanol and acetonitrile is 30-40: 15-5.
8. The method according to claim 4, wherein the volume ratio of the citric acid solution to the mixed solution of methanol and acetonitrile in the mobile phase is 50-60: 50-40.
9. The method according to claim 7, wherein the volume ratio of methanol to acetonitrile in the mixed solution of methanol and acetonitrile is 35: 10.
10. The method according to claim 8, wherein the volume ratio of the citric acid solution to the mixed solution of methanol and acetonitrile in the mobile phase is 55: 45.
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| CN112209895A (en) * | 2020-10-16 | 2021-01-12 | 深圳市祥根生物科技有限公司 | Preparation method of mosapride citrate impurity |
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Denomination of invention: A Detection Method for Five Key Impurities in Mosapride Citrate and Its Formulations Granted publication date: 20220930 Pledgee: Nanjing Bank Co.,Ltd. Nanjing North Branch Pledgor: NANJING BESTFORM PHARMTECH CO.,LTD. Registration number: Y2024980025145 |
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