CN112129878A - Analysis method of medical organic intermediate impurities - Google Patents
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- CN112129878A CN112129878A CN202011112338.8A CN202011112338A CN112129878A CN 112129878 A CN112129878 A CN 112129878A CN 202011112338 A CN202011112338 A CN 202011112338A CN 112129878 A CN112129878 A CN 112129878A
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- 239000012535 impurity Substances 0.000 title claims abstract description 41
- 238000004458 analytical method Methods 0.000 title claims abstract description 27
- 239000000543 intermediate Substances 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000001819 mass spectrum Methods 0.000 claims abstract description 17
- 239000012488 sample solution Substances 0.000 claims abstract description 17
- 239000012088 reference solution Substances 0.000 claims abstract description 13
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 8
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 7
- 238000012795 verification Methods 0.000 claims abstract description 5
- 238000010828 elution Methods 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000000523 sample Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 11
- 241000720974 Protium Species 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 8
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 claims description 8
- 238000001228 spectrum Methods 0.000 claims description 8
- 238000004949 mass spectrometry Methods 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000001133 acceleration Effects 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000011159 matrix material Substances 0.000 claims description 4
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 claims description 4
- 239000013558 reference substance Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 230000003595 spectral effect Effects 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000005481 NMR spectroscopy Methods 0.000 claims 1
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 8
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 229960005187 telmisartan Drugs 0.000 description 6
- 238000003908 quality control method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 241000446313 Lamella Species 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
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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
- G01N30/88—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
- G01N30/88—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
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- 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)
- Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
Abstract
The invention discloses an analysis method of medical organic intermediate impurities, which is characterized by comprising the following steps: step S1, preparing a sample solution, step S2, preparing a reference solution, step S3, carrying out HPLC chromatographic analysis, step S4, carrying out impurity content statistics, and step S5, and carrying out mass spectrum nuclear magnetic verification. The method for analyzing the impurities of the pharmaceutical organic intermediates disclosed by the invention has the advantages of higher accuracy, simpler and more convenient operation, high analysis efficiency, capability of effectively controlling the product quality and low analysis cost, and is suitable for analyzing most of the impurities of the pharmaceutical organic intermediates.
Description
Technical Field
The invention relates to the technical field of chemical drug analysis methods, in particular to an analysis method of organic intermediate impurities of a medicine.
Background
The diseases are caused by the old natural law of life and death, and the people are filled with thorns throughout life and are inevitable to suffer from the diseases. Particularly in recent years, with the increase of the stress from life and work, the acceleration of the pace of life and the increasing severity of environmental problems, more and more people suffer from the disease or diseases, which cause serious psychological and physiological burdens to them, and it is very critical to perform the targeted treatment of the disease by taking the medicine into the way.
At present, the drug therapy is still the main means of disease therapy, and the purity of the drug components directly determines the safety and efficacy of the drug. The purity of the medicine components depends on the preparation process of the medicine organic intermediate, and in the existing intermediate synthesis process of the medicines, whether the synthesis reaction is complete and the product quality is reliable directly determines the quality and the cost of the medicines.
At present, a plurality of methods for analyzing impurities of medical organic intermediates are commonly used in thin-layer chromatography, but the sensitivity of the existing thin-layer chromatography is relatively low, and the method for visually observing results is somewhat subjective and is easy to introduce artificial errors. And the spread distance of the lamella plates is limited, the separation situation is not optimal.
The Chinese patent with application number of 201810081672.8 relates to telmisartan detection, and discloses a high performance liquid chromatography analysis method and a detection method of impurities in telmisartan, wherein the analysis method can separately detect 8 impurities A, B, C, E, F, G, H, I in telmisartan and telmisartan medicines, the high performance liquid chromatography analysis method is used for detecting telmisartan medicine samples, whether the medicine contains one or more of the 8 impurities can be rapidly detected through one-time chromatographic analysis, and the detection of the content of the impurities is realized through the high performance liquid chromatography analysis, so that the aim of controlling the quality of medicines is fulfilled. The detection method greatly shortens the analysis time, is simple, reliable and accurate to operate, changes the factors of more operation steps, long analysis time, more interference factors and the like in the past, and is an effective means for quality control in telmisartan drug research and production processes. However, the accuracy of the analysis method is to be further improved due to problems of chromatographic analysis conditions and chromatographic columns, and the chromatographic columns are damaged greatly during the test process, thereby increasing the quality control cost.
Therefore, the development of a method for analyzing the impurities of the pharmaceutical organic intermediates, which has higher accuracy, simpler and more convenient operation and high analysis efficiency and can effectively control the product quality, is urgent.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the method for analyzing the impurities of the pharmaceutical organic intermediates, which has the advantages of higher accuracy, simpler and more convenient operation, high analysis efficiency, effective control on the product quality, low analysis cost and suitability for analyzing most of the impurities of the pharmaceutical organic intermediates.
In order to achieve the purpose, the invention adopts the technical scheme that: an analysis method of medical organic intermediate impurities is characterized by comprising the following steps:
step S1, preparing a sample solution: placing the medical organic intermediate sample in a volumetric flask, and dissolving with a certain solvent to a constant volume to obtain a sample solution of 6-10 mug/mL;
step S2, preparing a reference solution: putting the medicine organic intermediate pure substance into a volumetric flask, and performing constant volume by using the same solvent in the step S1 to obtain a reference substance solution with the same concentration;
step S3, HPLC chromatography: accurately measuring the sample solution prepared in the step S1 and the reference solution prepared in the step S2 with the same volume, respectively injecting the sample solution and the reference solution into a high performance liquid chromatograph, performing gradient elution, and respectively recording chromatograms;
step S4, counting the impurity content: estimating the content of impurities by comparing spectrograms and according to the proportion of spectral peak areas;
step S5, mass spectrum nuclear magnetic verification: and performing mass spectrum nuclear magnetic identification on the structure and the content of the sample by using MALDI-TOF and nuclear magnetic carbon spectrum.
Preferably, the solvent in step S1 is any one of ethanol, tetrahydrofuran, acetonitrile, acetone, dichloromethane, and dimethylsulfoxide.
Preferably, the same volume in step S3 is 1-3. mu.L.
Preferably, the chromatographic column for gradient elution in step S3 is a carbon octadecyl bonded silica gel filler chromatographic column.
Preferably, the column temperature of the gradient elution in step S3 is 35-60 ℃.
Preferably, the conditions of the gradient elution in step S3 are: 0-30min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 30-40min, 100% mobile phase B; 40-45min, 0 mobile phase A-95% mobile phase A, 100% mobile phase B-5% mobile phase B.
Preferably, the mobile phase a is methanol, and the mobile phase B is triethylamine.
Preferably, the flow rate of the gradient elution is: 0.3-0.8 mL/min.
Preferably, the detection wavelength of the gradient elution is: 230-.
Preferably, the condition for nuclear magnetic identification of mass spectrum in step S5 is: 2, 5-dihydroxy benzoic acid (DHB) is used as a sample mixing matrix, the acceleration voltage is 17-22kv in a positive ion mode, and the delay time is 90-120 ns; the scanning range of liquid chromatography-mass spectrometry is 1000-4500m/z, and the scanning range of direct mass spectrometry is extended to 10000-12000 m/z.
Preferably, the protium reagent used in the nuclear magnetic carbon spectrum is any one of protium dimethyl sulfoxide and protium chloroform.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the invention provides an analysis method of pharmaceutical organic intermediate impurities, which has the advantages of higher accuracy, simpler and more convenient operation, high analysis efficiency, effective control of product quality and low analysis cost, and is suitable for analyzing most pharmaceutical organic intermediate impurities.
Detailed Description
The following detailed description of preferred embodiments of the invention will be made.
An analysis method of medical organic intermediate impurities is characterized by comprising the following steps:
step S1, preparing a sample solution: placing the medical organic intermediate sample in a volumetric flask, and dissolving with a certain solvent to a constant volume to obtain a sample solution of 6-10 mug/mL;
step S2, preparing a reference solution: putting the medicine organic intermediate pure substance into a volumetric flask, and performing constant volume by using the same solvent in the step S1 to obtain a reference substance solution with the same concentration;
step S3, HPLC chromatography: accurately measuring the sample solution prepared in the step S1 and the reference solution prepared in the step S2 with the same volume, respectively injecting the sample solution and the reference solution into a high performance liquid chromatograph, performing gradient elution, and respectively recording chromatograms;
step S4, counting the impurity content: estimating the content of impurities by comparing spectrograms and according to the proportion of spectral peak areas;
step S5, mass spectrum nuclear magnetic verification: and performing mass spectrum nuclear magnetic identification on the structure and the content of the sample by using MALDI-TOF and nuclear magnetic carbon spectrum.
Preferably, the solvent in step S1 is any one of ethanol, tetrahydrofuran, acetonitrile, acetone, dichloromethane, and dimethylsulfoxide.
Preferably, the same volume in step S3 is 1-3. mu.L.
Preferably, the chromatographic column for gradient elution in step S3 is a carbon octadecyl bonded silica gel filler chromatographic column.
Preferably, the column temperature of the gradient elution in step S3 is 35-60 ℃.
Preferably, the conditions of the gradient elution in step S3 are: 0-30min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 30-40min, 100% mobile phase B; 40-45min, 0 mobile phase A-95% mobile phase A, 100% mobile phase B-5% mobile phase B.
Preferably, the mobile phase a is methanol, and the mobile phase B is triethylamine.
Preferably, the flow rate of the gradient elution is: 0.3-0.8 mL/min.
Preferably, the detection wavelength of the gradient elution is: 230-.
Preferably, the condition for nuclear magnetic identification of mass spectrum in step S5 is: 2, 5-dihydroxy benzoic acid (DHB) is used as a sample mixing matrix, the acceleration voltage is 17-22kv in a positive ion mode, and the delay time is 90-120 ns; the scanning range of liquid chromatography-mass spectrometry is 1000-4500m/z, and the scanning range of direct mass spectrometry is extended to 10000-12000 m/z.
Preferably, the protium reagent used in the nuclear magnetic carbon spectrum is any one of protium dimethyl sulfoxide and protium chloroform.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages: the invention provides an analysis method of pharmaceutical organic intermediate impurities, which has the advantages of higher accuracy, simpler and more convenient operation, high analysis efficiency, effective control of product quality and low analysis cost, and is suitable for analyzing most pharmaceutical organic intermediate impurities.
The invention will be further described with reference to specific examples, but the scope of protection of the invention is not limited thereto:
example 1
Embodiment 1 provides an analysis method of pharmaceutical organic intermediate impurities, which is characterized by comprising the following steps:
step S1, preparing a sample solution: placing the medical organic intermediate sample in a volumetric flask, and dissolving with a certain solvent to a constant volume to obtain a sample solution of 6 mug/mL;
step S2, preparing a reference solution: putting the medicine organic intermediate pure substance into a volumetric flask, and performing constant volume by using the same solvent in the step S1 to obtain a reference substance solution with the same concentration;
step S3, HPLC chromatography: accurately measuring the sample solution prepared in the step S1 and the reference solution prepared in the step S2 with the same volume, respectively injecting the sample solution and the reference solution into a high performance liquid chromatograph, performing gradient elution, and respectively recording chromatograms;
step S4, counting the impurity content: estimating the content of impurities by comparing spectrograms and according to the proportion of spectral peak areas;
step S5, mass spectrum nuclear magnetic verification: and performing mass spectrum nuclear magnetic identification on the structure and the content of the sample by using MALDI-TOF and nuclear magnetic carbon spectrum.
In step S1, the solvent is ethanol; the same volume is 1 μ L in step S3; the chromatographic column of the gradient elution in the step S3 is a carbon octadecyl bonded silica gel filler chromatographic column; the column temperature of the gradient elution described in step S3 was 35 ℃.
The conditions of the gradient elution in step S3 are: 10min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 30min, 100% mobile phase B; 40min, 0 mobile phase A-95% mobile phase A, 100% mobile phase B-5% mobile phase B.
The mobile phase A is methanol, and the mobile phase B is triethylamine.
Flow rate of the gradient elution: 0.3 mL/min; detection wavelength of the gradient elution: 230 nm.
The nuclear magnetic identification conditions of the mass spectrum in the step S5 are as follows: 2, 5-dihydroxy benzoic acid (DHB) is used as a sample mixing matrix, the acceleration voltage is 17kv in a positive ion mode, and the delay time is 90 ns; the scanning range of the liquid chromatography-mass spectrometry is 1000m/z, and the scanning range of the direct mass spectrometry is extended to 10000 m/z.
The protium reagent used in the nuclear magnetic carbon spectrum is protium dimethyl sulfoxide.
Example 2
Example 2 provides a method for analyzing pharmaceutical organic intermediate impurities, which is substantially the same as example 1 except that the gradient elution conditions in step S3 are as follows: 15min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 33min, 100% mobile phase B; 42min, mobile phase A of 0-95% mobile phase A, 100% mobile phase B-5% mobile phase B; the nuclear magnetic identification conditions of the mass spectrum in the step S5 are as follows: the accelerating voltage is 19kv, and the delay time is 100 ns; the scanning range of the liquid chromatography-mass spectrometry is 1500m/z, and the scanning range of the direct mass spectrometry is extended to 10500 m/z.
Example 3
Example 3 provides a method for analyzing pharmaceutical organic intermediate impurities, which is substantially the same as in example 1 except that the conditions of gradient elution in step S3 are as follows: 22min, 90% mobile phase A-70% mobile phase A, 10% mobile phase B-40% mobile phase B; 35min, 100% mobile phase B; 43min, mobile phase A of 0-95% mobile phase A, 100% mobile phase B-5% mobile phase B; the nuclear magnetic identification conditions of the mass spectrum in the step S5 are as follows: the accelerating voltage is 20kv, and the delay time is 105 ns; the scanning range of the liquid chromatography-mass spectrometry is 3500m/z, and the scanning range of the direct mass spectrometry is extended to 11000 m/z.
Example 4
Example 4 provides a method for analyzing impurities of pharmaceutical organic intermediates, which is substantially the same as in example 1 except that the conditions of gradient elution in step S3 are as follows: 25min, 90% mobile phase A-70% mobile phase A, 10% mobile phase B-40% mobile phase B; 38min, 100% mobile phase B; 44min, mobile phase A of 0-95% mobile phase A, 100% mobile phase B-5% mobile phase B; the nuclear magnetic identification conditions of the mass spectrum in the step S5 are as follows: the accelerating voltage is 21kv, and the delay time is 115 ns; the scanning range of the liquid chromatography-mass spectrometry is 4300m/z, and the scanning range of the direct mass spectrometry is extended to 11500 m/z.
Example 5
Example 5 provides a method for analyzing impurities of a pharmaceutical organic intermediate, which is substantially the same as in example 1, except that the conditions of gradient elution in step S3 are as follows: 30min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 40min, 100% mobile phase B; 45min, 0 mobile phase A-95% mobile phase A, 100% mobile phase B-5% mobile phase B; the nuclear magnetic identification conditions of the mass spectrum in the step S5 are as follows: the accelerating voltage is 22kv, and the delay time is 120 ns; the scanning range of the LC-MS is 4500m/z, and the scanning range of the direct mass spectrum is extended to 12000 m/z.
The above-mentioned embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (10)
1. An analysis method of medical organic intermediate impurities is characterized by comprising the following steps:
step S1, preparing a sample solution: placing the medical organic intermediate sample in a volumetric flask, and dissolving with a certain solvent to a constant volume to obtain a sample solution of 6-10 mug/mL;
step S2, preparing a reference solution: putting the medicine organic intermediate pure substance into a volumetric flask, and performing constant volume by using the same solvent in the step S1 to obtain a reference substance solution with the same concentration;
step S3, HPLC chromatography: accurately measuring the sample solution prepared in the step S1 and the reference solution prepared in the step S2 with the same volume, respectively injecting the sample solution and the reference solution into a high performance liquid chromatograph, performing gradient elution, and respectively recording chromatograms;
step S4, counting the impurity content: estimating the content of impurities by comparing spectrograms and according to the proportion of spectral peak areas;
step S5, mass spectrum nuclear magnetic verification: and performing mass spectrum nuclear magnetic identification on the structure and the content of the sample by using MALDI-TOF and nuclear magnetic carbon spectrum.
2. The method for analyzing impurities of a pharmaceutical organic intermediate according to claim 1, wherein the solvent in step S1 is any one of ethanol, tetrahydrofuran, acetonitrile, acetone, dichloromethane, and dimethylsulfoxide.
3. The method of claim 1, wherein the volume of step S3 is 1-3 μ L.
4. The method for analyzing the impurities of the pharmaceutical organic intermediates of claim 1, wherein the chromatographic column for gradient elution in step S3 is a carbon octadecyl bonded silica gel filler chromatographic column.
5. The method for analyzing impurities of a pharmaceutical organic intermediate according to claim 1, wherein the column temperature of the gradient elution in step S3 is 35-60 ℃.
6. The method of claim 1, wherein the gradient elution in step S3 is performed under the following conditions: 0-30min, 90% of mobile phase A-70% of mobile phase A, 10% of mobile phase B-40% of mobile phase B; 30-40min, 100% mobile phase B; 40-45min, 0 mobile phase A-95% mobile phase A, 100% mobile phase B-5% mobile phase B.
7. The method for analyzing the impurities of the pharmaceutical organic intermediates according to claim 6, wherein the mobile phase A is methanol and the mobile phase B is triethylamine.
8. The method of claim 1, wherein the gradient elution has a flow rate of: 0.3-0.8 mL/min; detection wavelength of the gradient elution: 230-.
9. The method for analyzing pharmaceutical organic intermediate impurities as claimed in claim 1, wherein the condition of mass nuclear magnetic resonance identification in step S5 is: 2, 5-dihydroxy benzoic acid (DHB) is used as a sample mixing matrix, the acceleration voltage is 17-22kv in a positive ion mode, and the delay time is 90-120 ns; the scanning range of liquid chromatography-mass spectrometry is 1000-4500m/z, and the scanning range of direct mass spectrometry is extended to 10000-12000 m/z.
10. The method for analyzing impurities in a pharmaceutical organic intermediate according to claim 1, wherein the protium reagent used in the nuclear magnetic carbon spectrum is protium dimethyl sulfoxide or protium chloroform.
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030835A (en) * | 2010-11-03 | 2011-04-27 | 北京佗林医药科技有限公司 | Radix Morindae officinalis extract, preparation method and applications thereof |
| CN102095808A (en) * | 2009-12-14 | 2011-06-15 | 重庆华邦制药股份有限公司 | Analysis method of related substances in Ebastine |
| CN103030605A (en) * | 2012-12-14 | 2013-04-10 | 贵州信邦制药股份有限公司 | Preparation method and detection method of febuxostat raw material |
| CN103175905A (en) * | 2011-12-20 | 2013-06-26 | 北京本草天源药物研究院 | Method for determining impurities in febuxostat and its preparation through high performance liquid chromatography |
| CN103822997A (en) * | 2014-03-20 | 2014-05-28 | 山东新时代药业有限公司 | Analysis and detection method for rivaroxaban intermediate |
| CN104698106A (en) * | 2015-03-21 | 2015-06-10 | 石家庄四药有限公司 | Detection method of related substances in chemical drug acotiamide hydrochloride hydrate |
| CN105277633A (en) * | 2014-07-26 | 2016-01-27 | 浙江仙琚制药股份有限公司 | Impurity detection analysis method of norethisterone derivatives and intermediates thereof |
| CN109239253A (en) * | 2018-09-21 | 2019-01-18 | 上海现代制药海门有限公司 | A kind of efficient liquid phase detection method of the impurity of Abacavir |
| CN109254097A (en) * | 2018-11-13 | 2019-01-22 | 重庆华邦胜凯制药有限公司 | The method of Z3 and relative substance in a kind of high performance liquid chromatography separation analysis Acrivastine bulk pharmaceutical chemicals intermediate Z3 |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
-
2020
- 2020-10-16 CN CN202011112338.8A patent/CN112129878A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102095808A (en) * | 2009-12-14 | 2011-06-15 | 重庆华邦制药股份有限公司 | Analysis method of related substances in Ebastine |
| CN102030835A (en) * | 2010-11-03 | 2011-04-27 | 北京佗林医药科技有限公司 | Radix Morindae officinalis extract, preparation method and applications thereof |
| CN103175905A (en) * | 2011-12-20 | 2013-06-26 | 北京本草天源药物研究院 | Method for determining impurities in febuxostat and its preparation through high performance liquid chromatography |
| CN103030605A (en) * | 2012-12-14 | 2013-04-10 | 贵州信邦制药股份有限公司 | Preparation method and detection method of febuxostat raw material |
| CN103822997A (en) * | 2014-03-20 | 2014-05-28 | 山东新时代药业有限公司 | Analysis and detection method for rivaroxaban intermediate |
| CN105277633A (en) * | 2014-07-26 | 2016-01-27 | 浙江仙琚制药股份有限公司 | Impurity detection analysis method of norethisterone derivatives and intermediates thereof |
| CN104698106A (en) * | 2015-03-21 | 2015-06-10 | 石家庄四药有限公司 | Detection method of related substances in chemical drug acotiamide hydrochloride hydrate |
| CN109239253A (en) * | 2018-09-21 | 2019-01-18 | 上海现代制药海门有限公司 | A kind of efficient liquid phase detection method of the impurity of Abacavir |
| CN109254097A (en) * | 2018-11-13 | 2019-01-22 | 重庆华邦胜凯制药有限公司 | The method of Z3 and relative substance in a kind of high performance liquid chromatography separation analysis Acrivastine bulk pharmaceutical chemicals intermediate Z3 |
| CN110128293A (en) * | 2019-04-09 | 2019-08-16 | 武汉武药制药有限公司 | A kind of medicine intermediate impurity and the preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 邹纯才: "《药物分析 第2版》", 31 January 2018, 江苏凤凰科学技术出版社 * |
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