CN109507345A - The method of separating and assaying of rivastigmine intermediate and its impurity - Google Patents
The method of separating and assaying of rivastigmine intermediate and its impurity Download PDFInfo
- Publication number
- CN109507345A CN109507345A CN201710831727.8A CN201710831727A CN109507345A CN 109507345 A CN109507345 A CN 109507345A CN 201710831727 A CN201710831727 A CN 201710831727A CN 109507345 A CN109507345 A CN 109507345A
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- Prior art keywords
- ethyl
- methylamino formyl
- formyl chloride
- temperature
- chromatographic column
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- 238000000034 method Methods 0.000 title claims abstract description 32
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 title claims abstract description 7
- 229960004136 rivastigmine Drugs 0.000 title claims abstract description 7
- 239000012535 impurity Substances 0.000 title abstract description 3
- XZVYDRLPXWFRIS-UHFFFAOYSA-N n-ethyl-n-methylcarbamoyl chloride Chemical compound CCN(C)C(Cl)=O XZVYDRLPXWFRIS-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000000926 separation method Methods 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 14
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 238000004817 gas chromatography Methods 0.000 claims abstract description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 17
- 239000007789 gas Substances 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000012159 carrier gas Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 239000007924 injection Substances 0.000 claims description 9
- 239000013558 reference substance Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 239000012085 test solution Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims 1
- 229910052734 helium Inorganic materials 0.000 claims 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims 1
- 229950010673 rivastigmine hydrogen tartrate Drugs 0.000 abstract description 8
- GWHQHAUAXRMMOT-MBANBULQSA-N rivastigmine tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 GWHQHAUAXRMMOT-MBANBULQSA-N 0.000 abstract description 8
- 239000002202 Polyethylene glycol Substances 0.000 abstract 1
- 238000007086 side reaction Methods 0.000 abstract 1
- -1 N- ethyl-N-methylamino formyl Chemical group 0.000 description 9
- 230000014759 maintenance of location Effects 0.000 description 6
- 238000005070 sampling Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000012490 blank solution Substances 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical class NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-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
- 230000002164 acetylcholinergic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- 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
Abstract
The invention belongs to analytical chemistry fields, the invention discloses a kind of with gas chromatography quick separating detection rivastigmine intermediate N- ethyl-N-methylamino formyl chloride and in relation to the method for substance, using polyethylene glycol capillary chromatographic column, flame ionization ditector, sample direct injected temperature-programmed mode, it can be with the content of separation determination N- ethyl-N-methylamino formyl chloride, to reach effective control to N- ethyl-N-methylamino formyl chloride, reduce the generation of side reaction and the generation of impurity, improve product yield, and then effectively control the purity of rivastigmine-hydrogentartrate.The method of the present invention specificity is strong, and accuracy is high, and durability is good, and easy to operate quick.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular among gas chromatography separation determination rivastigmine-hydrogentartrate
Body and its method in relation to substance.
Background technique
Rivastigmine-hydrogentartrate is a kind of carbamic acid class brain selectivity acetylcholinesterase inhibitor, by delaying gallbladder
Degradation of the alkali neuron to release acetylcholine, and cholinergic nerve is promoted to conduct.Rivastigmine-hydrogentartrate can improve Ah
The cognition dysfunction that Alzheimer's disease patient's cholinergic mediates, can also slow down the light powder sample precursor protein fragments of amyloid beta-
Formation, and amyloid plaques are one of main ingredient pathological characters of Alzheimer disease.N- ethyl-N-methylamino formyl chloride is
The synthetic intermediate of rivastigmine-hydrogentartrate, molecular formula C4H8CINO, structural formula are as follows:
The intermediate that N- ethyl-N-methylamino formyl chloride is synthesized as rivastigmine-hydrogentartrate, needing strict control, it contains
Amount.According to N- ethyl-N-methylamino formyl chloride synthesis technology, the related substance being related to during the preparation process has benzaldehyde,
Accurately separation determination N- ethyl-N-methylamino formyl chloride and its related substance, to control rivastigmine-hydrogentartrate drug
Quality has great meaning.
Summary of the invention
The purpose of the present invention is to provide a kind of separation detection rivastigmine intermediate N- ethyl-N-methyl ammonia
Base formyl chlorinity and method in relation to substance guarantee to reach effective control to N- ethyl-N-methylamino formyl chloride
The chemical purity of N- ethyl-N-methylamino formyl chloride, and then control the quality of rivastigmine-hydrogentartrate.
A kind of separation determination N- ethyl-N-methylamino formyl chlorinity of the present invention and the method in relation to substance,
It is that the capillary chromatographic column of suitable polarity, flame ionization ditector, direct injected are selected using gas chromatographic analysis technique
Temperature-programmed mode completes separation and detection.
Above-mentioned described chromatographic column is selected from the brands such as Agilent, OHIO VALLEY, Phenomenex or SGE.
Above-mentioned described chromatographic column is highly polar polyethylene glycols capillary chromatographic column.
Method of separating and assaying of the present invention can be realized in accordance with the following methods:
1) accurate to measure N- ethyl-N-methylamino formyl chloride and benzaldehyde sample is each in right amount in different sample injection bottles, as confession
Test product separately takes N- ethyl-N-methylamino formyl chloride reference substance, the reference substance for being 10 ~ 100mg/ml at concentration with dilution in acetonitrile
Solution.
2) setting injector temperature is 200 DEG C ~ 300 DEG C, and flow rate of carrier gas is 0.8 ~ 1.5mL/min, programmed temperature method, heating
Program is 25 °C ~ 35 DEG C of initial temperature, 5 ~ 10min of constant temperature, with 3 ~ 8 °C of heating rate per minute to 150 °C, then with per minute
For 5 ~ 10 DEG C of heating rate to 200 DEG C, 5 ~ 10min of constant temperature, detector temperature is 250 ~ 350 DEG C, and split ratio is 10:1 ~ 50:1.
3) each 0.1~0.5 μ L of the test solution and control solution in 1) is taken, gas chromatograph is injected, using peak face
Product normalization method completes the separation determination of N- ethyl-N-methylamino formyl chloride and benzaldehyde.Wherein:
The model of gas chromatograph, has no special requirements, and the gas chromatograph that the present invention uses is Agilent 7890A gas-chromatography
Instrument
Detector: flame ionization ditector
Chromatographic column: ZB-WAX capillary chromatographic column (15m × 0.32mm × 0.5 μm)
Injector temperature: 250 DEG C;
Detector temperature: 300 DEG C;
Carrier gas (nitrogen) flow velocity: 1.0mL/min;
Split ratio: 50:1;
Sampling volume: 0.2 μ L
Column temperature rise program:
。
The present invention uses gas chromatography, selects ZB-WAX capillary chromatographic column (15m × 0.32mm × 0.5 μm) can be quickly
It efficiently separates measurement N- ethyl-N-methylamino formyl chlorinity and its related substance benzaldehyde, the present invention solves N- second
The separation determination of base-N- methyl amido formyl chloride and its related substances benzaldehyde, to reach N- ethyl-N-methylamino formyl
Effective control of chlorinity guarantees the chemical purity of N- ethyl-N-methylamino formyl chloride synthetic product.The results are shown in attached figure 1 ~ and 4.
Detailed description of the invention
The gas chromatogram of solvent (acetonitrile) when Fig. 1 is embodiment 1;
The gas chromatogram of N- ethyl-N-methylamino formyl chloride reference substance solution when Fig. 2 is embodiment 1;
The gas chromatogram of benzaldehyde when Fig. 3 is embodiment 1;
The gas chromatogram of N- ethyl-N-methylamino formyl chloride when Fig. 4 is embodiment 1;
The gas chromatogram of N- ethyl-N-methylamino formyl chloride when Fig. 5 is embodiment 2;
The gas chromatogram of N- ethyl-N-methylamino formyl chloride when Fig. 6 is embodiment 3.
Specific embodiment:
Following embodiment is not limited to the range of this implementation for further understanding the present invention.Below by way of example forms, to this
It invents the rivastigmine intermediate N- ethyl-N-methylamino formyl chloride being related to and its related substance-measuring method is made
It is further to be described in detail, but the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below, it is all to be based on
The technology that above content of the present invention is realized all belongs to the scope of the present invention.
Embodiment 1
Instrument and condition
Chromatograph: Agilent 7890A gas chromatograph;
Detector: flame ionization ditector;
Chromatographic column: DB-WAX capillary chromatographic column (Agilent, 15m × 0.32mm × 0.5 μm)
Injector temperature: 250 DEG C;
Detector temperature: 300 DEG C;
Carrier gas (nitrogen) flow velocity: 1.0mL/min;
Split ratio: 50:1;
Sampling volume: 0.2 μ L
Column temperature rise program:
。
Experimental procedure
Precision measures N- ethyl-N-methylamino formyl chloride and benzaldehyde sample is each in right amount in different sample injection bottles, as examination
Product separately take N- ethyl-N-methylamino formyl chloride 200mg, measure in 2ml capacity, are settled to scale with dilution in acetonitrile, shake up,
Reference substance solution as N- ethyl-N-methylamino formyl chloride.Separately taking acetonitrile is blank solution.It is carried out by above-mentioned chromatographic condition
Analysis records chromatogram, and the content of N- ethyl-N-methylamino formyl chloride is calculated by areas of peak normalization method.The results are shown in attached figure 1
~ 4, Fig. 1 are solvent acetonitrile chromatogram;Fig. 2 is N- ethyl-N-methylamino formyl chloride reference substance solution chromatogram.Fig. 3 is benzene first
Aldehyde chromatogram, Fig. 4 are N- ethyl-N-methylamino formyl chloride chromatogram.Retention time is the chromatographic peak of 20.153min in Fig. 4
For N- ethyl-N-methylamino formyl chloride, the chromatographic peak that retention time is 22.161min is benzaldehyde.Fig. 1 ~ Fig. 4 shows: this
Inventing the method provided can fast and effeciently separation determination N- ethyl-N-methylamino formyl chloride and its related substance benzaldehyde.
Embodiment 2
Instrument and condition
Chromatograph: Agilent 7890A gas chromatograph;
Detector: flame ionization ditector;
Chromatographic column: ZB-WAX capillary chromatographic column (Phenomenex, 15m × 0.32mm × 0.5 μm)
Injector temperature: 230 DEG C;
Detector temperature: 300 DEG C;
Carrier gas (nitrogen) flow velocity: 1.2mL/min;
Split ratio: 50:1;
Sampling volume: 0.2 μ L
Column temperature rise program:
。
Experimental procedure
Precision measures N- ethyl-N-methylamino formyl chloride in right amount in sample injection bottle, as test solution, by above-mentioned chromatostrip
Part is analyzed, and chromatogram is recorded, and the content of N- ethyl-N-methylamino formyl chloride, spectrogram are calculated by areas of peak normalization method
See attached drawing 5, the chromatographic peak that wherein retention time is 18.290min is N- ethyl-N-methylamino formyl chloride, and retention time is
20.313min chromatographic peak be benzaldehyde.Fig. 5 the result shows that, method provided by the invention can fast and effeciently separation determination N-
Ethyl-N-methylamino formyl chloride and its related substance benzaldehyde, and can accurately to N- ethyl-N-methylamino formyl chloride into
Row quantitative detection, to reach effective control to N- ethyl-N-methylamino formyl chloride.
Embodiment 3
Instrument and condition
Chromatograph: Agilent 7890A gas chromatograph;
Detector: flame ionization ditector;
Chromatographic column: ZB-WAX capillary chromatographic column (Phenomenex, 15m × 0.32mm × 0.5 μm)
Injector temperature: 250 DEG C;
Detector temperature: 300 DEG C;
Carrier gas (nitrogen) flow velocity: 1.0mL/min;
Split ratio: 50:1;
Sampling volume: 0.2 μ L
Column temperature rise program:
。
Experimental procedure
Precision measures N- ethyl-N-methylamino formyl chloride in right amount in sample injection bottle, as test sample.By above-mentioned chromatographic condition into
Row analysis, records chromatogram, and the content of N- ethyl-N-methylamino formyl chloride is calculated by areas of peak normalization method.Spectrogram is shown in attached
Fig. 6, the chromatographic peak that wherein retention time is 20.161min are N- ethyl-N-methylamino formyl chloride, and retention time is
22.153min chromatographic peak be benzaldehyde.Fig. 6 the result shows that, method provided by the invention can fast and effeciently separation determination N-
Ethyl-N-methylamino formyl chloride and benzaldehyde, and quantitative inspection accurately can be carried out to N- ethyl-N-methylamino formyl chloride
It surveys, to reach effective control to N- ethyl-N-methylamino formyl chloride.
The present invention separates the rivastigmine intermediate N- ethyl-N-methylamino formyl chloride and its related substance
The following items of measuring method are verified:
System suitability experiment
Precision measures N- ethyl-N-methylamino formyl chloride and benzaldehyde sample is each in right amount in different sample injection bottles, as examination
Product separately take N- ethyl-N-methylamino formyl chloride chlorine 200mg, measure in 2ml capacity, are settled to scale with dilution in acetonitrile, shake
Even, as acyl chlorides reference substance solution.Separately taking acetonitrile is blank solution.Gas-chromatography point is carried out by the chromatographic condition of embodiment 1
Analysis records chromatogram.By separating degree between the visible ethyl-N-methylamino of the N- with this condition formyl chloride in Fig. 1 ~ 4 and benzaldehyde
Well, solvent does not interfere the measurement of N- ethyl-N-methylamino formyl chlorinity.
Sample introduction repetitive test
Precision weighs appropriate N- ethyl-N-methylamino formyl chloride pure sample in sample injection bottle, as test sample, by embodiment 1
Chromatographic condition repeats sample introduction 6 times, investigates the repeatability of method.It can be added by result, this method sample introduction repeatability is good
。
Quantitative limit, detection limit
Under the chromatographic condition of embodiment 1, the N- ethyl-N-methylamino formyl chloride reference substance that precision measures under specificity item is molten
Appropriate liquid is diluted step by step with acetonitrile, until response is 10 times of noise, using the concentration as N- ethyl-N-methylamino formyl
The quantitative limit of chlorine.Continue to dilute with acetonitrile, until response is 3 times of noise, using the concentration as N- ethyl-N-methylamino first
The detection of acyl chlorides limits.As a result as shown in the table:
。
Durability
By chromatographic conditions such as fine tuning heating rate, initial column temperature, flow rate of carrier gas, the durability of method has further been investigated.Knot
Fruit discovery, this method is to durable under the conditions of heating rate ± 1 DEG C/min, initial temperature ± 5 DEG C, flow rate of carrier gas ± 2ml/min etc.
Property is good, as a result as shown above.
Test sample stability
Precision weighs a certain amount of N- ethyl-N-methylamino formyl chloride pure sample in sample injection bottle, places at room temperature, respectively at
0h, 2h, 4h, 6h, 8h, 10h, 12h sampling, inject in high performance liquid chromatograph.It is investigated by the chromatographic condition sample introduction of embodiment 1.
The result shows that sample is to be placed at room temperature for 12 hours internal stabilities good.
Claims (7)
1. it is a kind of with gas chromatography separation detection rivastigmine intermediate N- ethyl-N-methylamino formyl chloride and
Method in relation to substance, it is characterised in that: use gas chromatography, capillary chromatographic column, flame ionization ditector, directly
Injection procedure heating mode completes separation and detection.
2. method of separating and assaying according to claim 1, it is Pheomenex, Agilent, OHIO that chromatographic column, which is selected from brand,
The chromatographic column of VALLEY or SGE.
3. method of separating and assaying according to claim 1, chromatographic column is highly polar or middle polarity class capillary chromatographic column.
4. method of separating and assaying according to claim 3, chromatographic column preferably uses highly polar polyethylene glycols capillary chromatography
Column.
5. method of separating and assaying according to claim 1, which is characterized in that including the following steps:
Precision measures N- ethyl-N-methylamino formyl chloride and benzaldehyde sample is each in right amount in different sample injection bottles, as examination
Product separately take N- ethyl-N-methylamino formyl chloride reference substance, molten at the reference substance that concentration is 10 ~ 100mg/ml with dilution in acetonitrile
Liquid;
It is 200 DEG C ~ 300 DEG C that injector temperature, which is arranged, and flow rate of carrier gas is 0.8 ~ 1.5mL/min, and programmed temperature method, temperature program is
25 °C ~ 35 DEG C of initial temperature, 5 ~ 10min of constant temperature, with 3 ~ 8 °C of heating rate per minute to 150 °C, then with 5 ~ 10 DEG C per minute
Heating rate to 200 DEG C, 5 ~ 10min of constant temperature, detector temperature is 250 ~ 350 DEG C, and split ratio is 10:1 ~ 50:1;
3) each 0.1~0.5 μ L of the test solution and control solution in 1) is taken, gas chromatograph is injected, is returned using peak area
One changes the separation determination that method completes N- ethyl-N-methylamino formyl chloride and benzaldehyde.
6. method for separating and analyzing according to claim 5, carrier gas described in step 2 is nitrogen or helium.
7. method for separating and analyzing according to claim 5, programmed temperature method described in step 2, the preferably following journey that heats up
Sequence: 35 DEG C of initial temperature, constant temperature 5min, with 5 °C of heating rate per minute to 150 °C, then with 10 DEG C of heating speed per minute
Rate is to 200 DEG C, constant temperature 10min.
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Cited By (1)
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CN114740103A (en) * | 2022-03-16 | 2022-07-12 | 天津键凯科技有限公司 | Polydocanol oligomer distribution detection method |
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Denomination of invention: Separation and Determination Method of Intermediate and Impurities of Carbalatine Bitartrate Granted publication date: 20220805 Pledgee: Sanya Rural Commercial Bank Co.,Ltd. Pledgor: AVENTIS PHARMA (HAINAN) Co.,Ltd. Registration number: Y2024980014810 |