CN109507344A - Rivastigmine intermediate and its method for separating and detecting in relation to substance - Google Patents
Rivastigmine intermediate and its method for separating and detecting in relation to substance Download PDFInfo
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- CN109507344A CN109507344A CN201710831690.9A CN201710831690A CN109507344A CN 109507344 A CN109507344 A CN 109507344A CN 201710831690 A CN201710831690 A CN 201710831690A CN 109507344 A CN109507344 A CN 109507344A
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- 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
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- 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
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Abstract
The invention belongs to analytical chemistry fields, analysis rivastigmine intermediate 3-(1- dimethylaminoethyl is separated with liquid chromatography the invention discloses a kind of) phenol and its in relation to the method for substance, this method is using octadecylsilane chemically bonded silica as the chromatographic column of filler, using a certain proportion of buffer salt-organic phase as mobile phase, 3-(1- dimethylaminoethyl can be quantitative determined) phenol and its content in relation to substance, to which effectively control synthesizes the purity of reactant during rivastigmine-hydrogentartrate, reduce the generation of side reaction and the generation of impurity, improve product yield.The method of the present invention specificity is strong, and accuracy is high, easy to operate.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular to a kind of among HPLC separation determination rivastigmine-hydrogentartrate
Body and its analysis 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 pass to.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.Rivastigmine intermediate
Entitled (3-(1- dimethylaminoethyl) phenol of chemistry, molecular formula.Its chemical structural formula are as follows:
。
During synthesizing rivastigmine-hydrogentartrate, need to control the purity of some key intermediates, to reduce side reaction
Generation and impurity generation, to improve product yield and purity.
Synthesizing the related substance that the compound is related to has 2, respectively m-hydroxy acetophenone (in relation to substance A) and 3-(1- first ammonia
Base ethyl) phenol (related substance B), structural formula is respectively as follows:
The related substance B of related substance A.
The chemical purity of rivastigmine intermediate is controlled, in the synthesis of finished product rivastigmine-hydrogentartrate
And its quality controlling party face has important practical significance.
Summary of the invention
The purpose of the present invention is to provide a kind of separation determination rivastigmine intermediate 3-(1- dimethylamino second
Base) phenol and its HPLC analytical method in relation to substance, to guarantee the change of rivastigmine intermediate
Purity is learned, the generation of side reaction and the generation of impurity are reduced, to realize the quality control of its finished product rivastigmine-hydrogentartrate.
Use high performance liquid chromatography separation detection 3-(1- dimethylaminoethyl described in this method) phenol and its related substance
Method is the chromatographic column for using octadecylsilane chemically bonded silica as filler, is carried out by mobile phase of buffer salt solution-organic phase
Isocratic elution.
Above-mentioned described chromatographic column using octadecylsilane chemically bonded silica as filler, chromatographic column be selected from Alltima, Apollo or
The brands such as Agela, preferably Apollo brand.
Above-mentioned described organic phase is selected from one or more of following compound: methanol, acetonitrile, isopropanol, tetrahydrofuran etc.,
It is preferred that acetonitrile or methanol solution.
In above-mentioned described method, buffer salt solution is selected from phosphate, formates, acetate, perchlorate, preferably phosphate.
The concentration of buffer salt solution is 0.01~0.1mol/L.
In above-mentioned described method, the ion-pairing agent for being 5mmol/L ~ 10mmol/L comprising concentration in buffer salt solution is selected from
Lauryl sodium sulfate, perfluorooctane sulfonate, sodium heptanesulfonate, preferably sodium dodecyl sulfate.
Method for separating and analyzing of the present invention can be realized in accordance with the following methods:
(1) 3-(1- dimethylaminoethyl is taken) appropriate phenol with mobile phase dissolved dilution is configured to every 1mL diformazan containing 3-(1- ammonia
Base ethyl) phenol 0.1~1 .0mg sample solution；
(2) setting flow rate of mobile phase is 1.0ml/min, and Detection wavelength is 210 ~ 240 nm, column temperature: 20 ~ 30 DEG C；
(3) take 10 μ l of sample solution in (1) to inject liquid chromatograph, complete 3-(1- dimethylaminoethyl) phenol and its have
Close the separation and measurement of substance.Wherein:
High performance liquid chromatograph model has no special requirements, and the present invention uses Shimadzu high performance liquid chromatograph: LC-20AT pump；SPD-
M20A detector；SIL-20AC autosampler；CTO-10ASVP column oven；DGU-20A3Degasser；CBM-20A controller；
Chromatographic column: C18 (Apollo, 250 mm × 4.6 mm, 5 μm)；
Mobile phase: phosphate buffer (0.01mol/L sodium dihydrogen phosphate adds 5mmol/L lauryl sodium sulfate)-acetonitrile (60
: 40)；
Flow velocity: 1.0ml/min；
Detection wavelength: 218 nm；
Column temperature: room temperature；
Sampling volume: 10 μ l.
The present invention uses octadecylsilane chemically bonded silica for the chromatographic column of filler, phosphate buffer (containing ion-pairing agent)-
Acetonitrile is that mobile phase carries out gradient elution, can efficiently separate 3-(1- dimethylaminoethyl) phenol and its related substance, accurately
Measure the chemical purity of rivastigmine intermediate；The present invention solves rivastigmine intermediate 3-(1-
Dimethylaminoethyl) phenol solution and its separation determination problem in relation to substance, it is ensured that 3-(1- dimethylaminoethyl) phenol
Chemical purity, to ensure that quality controllable (result is shown in attached drawing) of rivastigmine-hydrogentartrate.
Detailed description of the invention:
Rivastigmine intermediate and its related substance HPLC figure when Fig. 1 is embodiment 1；
Rivastigmine intermediate and its related substance HPLC figure when Fig. 2 is embodiment 2；
Solvent HPLC figure when Fig. 3 is embodiment 3；
Rivastigmine intermediate when Fig. 4 is embodiment 3 and its HPLC figure in relation to substance；
The HPLC figure of rivastigmine intermediate when Fig. 5 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
Invent the separation 3-(1- dimethylaminoethyl that is related to) phenol and its method in relation to substance be described in further detail, but not
The range that this should be interpreted as to the above-mentioned theme of the present invention is only limitted to example below, all to be realized based on above content of the present invention
Technology all belongs to the scope of the present invention.
Embodiment 1
Instrument and condition:
Shimadzu high performance liquid chromatograph: LC-20AT pump；SPD-M20A detector；SIL-20AC autosampler；CTO-10ASVP
Column oven；DGU-20A3Degasser；CBM-20A controller；
Chromatographic column: C18 (Apollo, 250 mm × 4.6 mm, 5 μm)；
Mobile phase: phosphate buffer (0.01mol/L sodium dihydrogen phosphate adds 0.005mol/L lauryl sodium sulfate)-acetonitrile
(60: 40)；
Flow velocity: 1.0ml/min；
Detection wavelength: 218 nm；
Column temperature: room temperature；
Sampling volume: 10 μ l.
Experimental procedure:
Take rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol and its related substance it is appropriate, mixed with flowing
Solution dilution, is configured to every 1mL dimethylaminoethyl containing 3-(1-) phenol and its sample solution in relation to 0.1~1 .0mg of substance.
Efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, records chromatogram.The results are shown in attached figure 1, retention time 12.014min in Fig. 1
Chromatographic peak be rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol chromatographic peak, retention time 5.277min
Chromatographic peak be m-hydroxy acetophenone, the chromatographic peak of retention time 11.176min is 3-(1- methylaminoethyl) phenol.By Fig. 1
It is found that under this condition, the associated substance of rivastigmine intermediate, which can be realized, to be kept completely separate.
Embodiment 2
Instrument and condition:
Shimadzu high performance liquid chromatograph: LC-20AT pump；SPD-M20A detector；SIL-20AC autosampler；CTO-10ASVP
Column oven；DGU-20A3Degasser；CBM-20A controller；
Chromatographic column: C18 (Apollo, 250 mm × 4.6 mm, 5 μm)；
Mobile phase: phosphate buffer (0.01mol/L sodium dihydrogen phosphate adds 0.005mol/L lauryl sodium sulfate)-acetonitrile
(55:45)；
Flow velocity: 1.0ml/min；
Detection wavelength: 218m；
Column temperature: room temperature；
Sampling volume: 10 μ l.
Experimental procedure:
Take rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol and its related substance it is appropriate, mixed with flowing
Solution dilution, is configured to every 1mL dimethylaminoethyl containing 3-(1-) phenol and its sample solution in relation to 0.1~1 .0mg of substance.
Efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, records chromatogram.The results are shown in attached figure 2, retention time 7.478min in Fig. 2
Chromatographic peak is rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol chromatographic peak, retention time 4.656min's
Chromatographic peak is m-hydroxy acetophenone, and the chromatographic peak of retention time 6.885min is 3-(1- methylaminoethyl) phenol.It can by Fig. 2
Know, under this condition, the associated substance realization of rivastigmine intermediate is kept completely separate.
Embodiment 3
Instrument and condition:
Shimadzu high performance liquid chromatograph: LC-20AT pump；SPD-M20A detector；SIL-20AC autosampler；CTO-10ASVP
Column oven；DGU-20A3Degasser；CBM-20A controller；
Chromatographic column: C18 (Alltima, 250 mm × 4.6 mm, 5 μm)；
Mobile phase: phosphate buffer (0.01mol/L sodium dihydrogen phosphate adds 0.005mol/L lauryl sodium sulfate)-acetonitrile
(65:35)；
Flow velocity: 0.8ml/min；
Detection wavelength: 218m；
Column temperature: room temperature；
Sampling volume: 10 μ l.
Experimental procedure:
Take rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol and its related substance it is appropriate, mixed with flowing
Solution dilution, is configured to every 1mL dimethylaminoethyl containing 3-(1-) phenol and its sample solution in relation to 0.1~1 .0mg of substance.
Efficient liquid phase chromatographic analysis is carried out by above-mentioned condition, records chromatogram.The results are shown in attached figure 3 ~ chromatogram of 5, the Fig. 3 for solvent, Fig. 4
The chromatographic peak of middle retention time 25.484min is rivastigmine intermediate 3-(1- dimethylaminoethyl) phenol chromatography
Peak, the chromatographic peak of retention time 6.230min are m-hydroxy acetophenone, and the chromatographic peak of retention time 23.625min is 3-(1- first
Amino-ethyl) phenol.The chromatographic peak that retention time is 25.354min in Fig. 5 is rivastigmine intermediate 3-(1- bis-
Methylaminoethyl) phenol chromatographic peak.By Fig. 3 ~ Fig. 5 it is found that under this condition, rivastigmine intermediate is associated
Substance can be realized and is kept completely separate.
To above-mentioned rivastigmine intermediate and its analysis method in relation to substance is verified as follows:
1, system suitability
Take 3-(1- dimethylaminoethyl) phenol and its related substance it is appropriate, use methanol sample dissolution respectively, be configured to containing 3-(1-
Dimethylaminoethyl) phenol about 0.1 mg/mL and each mixing sample solution in relation to about 20 μ g/mL of substance.By embodiment 1
Chromatographic condition carries out separation determination, records chromatogram.As shown in Figure 1, with this condition, 3-(1- dimethylaminoethyl) phenol and
Its chromatographic peak peak shape in relation to substance is good, and separating degree meets the requirements.
2, sample introduction repeatability
Taking 3-(1- dimethylaminoethyl) sample solution of phenol by the chromatographic condition of embodiment 1 repeats 6 needle of sample introduction, investigate sample
Sample introduction repeatability when product quantitative determine.By result as it can be seen that retention time and peak area are without significant change, RSD% value is conformed to
It asks, sample introduction repeatability is good.
| Time (min) | t1 | t2 | t3 | t4 | t5 | t6 | RSD% |
| Related substance A | 5.332 | 5.341 | 5.342 | 5.344 | 5.348 | 5.354 | 0.14 |
| Related substance B | 11.637 | 11.687 | 11.693 | 11.701 | 11.714 | 11.728 | 0.27 |
| 3-(1- dimethylaminoethyl) phenol | 12.475 | 12.531 | 12.538 | 12.547 | 12.562 | 12.577 | 0.28 |
；
| Peak area | A1 | A2 | A3 | A4 | A5 | A6 | RSD% |
| Related substance A | 1591473 | 1592338 | 1592835 | 1594151 | 1593334 | 1594264 | 0.07 |
| Related substance B | 425471 | 424998 | 424733 | 425233 | 425563 | 424615 | 0.09 |
| 3-(1- dimethylaminoethyl) phenol | 2272144 | 2273138 | 2272758 | 2273188 | 2274957 | 2274145 | 0.04 |
3, stability of solution
Take 3-(1- dimethylaminoethyl) phenol sample solution, at room temperature, by the chromatographic condition of embodiment 1, respectively at
0,4,9,12,14 hours sample introductions, the stability of solution when investigating sample amounts measurement, by result as it can be seen that the test solution exists
Stablize in 24 hours.
6, quantitative limit
Under the conditions of embodiment 1,3-(1- dimethylaminoethyl is taken) appropriate phenol, add flowing phased soln and dilutes step by step, until
The ratio of signal and noise is about 10:1.By result as it can be seen that detection limit is nanogram level, meet detection needs.
| Sample | Quantitative limit concentration (ng/ μ l) |
| 3-(1- dimethylaminoethyl) phenol | 0.17 |
7, detection limit
Under the conditions of embodiment 1, above-mentioned quantitative limit strength solution dilutes step by step, until the ratio of signal and noise is about 3:
1.By result as it can be seen that detection is limited to nanogram level, meet detection needs.
| Sample | Detection limit concentration (ng/ μ l) |
| 3-(1- dimethylaminoethyl) phenol | 0.05 |
8, durability
We have further investigated the durability of flow velocity, column temperature.As a result, it has been found that when changing flow velocity, column temperature, each chromatographic peak peak face
Product is slightly changed, and can be efficiently separated between each chromatographic peak, theoretical cam curve meets the requirements.This method is durable to flow velocity, column temperature
Property is good.
Claims (9)
1. liquid chromatography separation detection rivastigmine-hydrogentartrate 3-(1- dimethylaminoethyl) phenol and its related substance
Method, it is characterised in that: use the chromatographic column using octadecylsilane chemically bonded silica as filler, be stream with buffer salt-organic phase
It is dynamic mutually to carry out isocratic elution.
2. method for separating and analyzing according to claim 1, described chromatographic column is selected from Alltima, Apollo or Agela etc.
Brand.
3. method for separating and analyzing according to claim 1, the organic phase in described mobile phase is in following compound
One or more: methanol, acetonitrile, isopropanol, tetrahydrofuran etc., preferably acetonitrile or methanol solution.
4. method of separating and assaying according to claim 1, the buffer salt solution in described mobile phase is selected from phosphate, first
Hydrochlorate, acetate, perchlorate, preferably phosphate.
5. method of separating and assaying according to claim 4, the concentration of described buffer salt solution is 0.01~0.1mol/L.
6. the method for separating and analyzing according to claim 1, described mobile phase ratio are as follows: buffer salt-organic phase=40:
60。
7. the method for separating and analyzing according to claim 1, in mobile phase in buffer salt solution comprising concentration be 5mmol/L ~
The ion-pairing agent of 10mmol/L is selected from lauryl sodium sulfate, perfluorooctane sulfonate, sodium heptanesulfonate, preferably dodecyl sulphur
Sour sodium.
8. the method for separating and analyzing according to claim 1, it is characterised in that including the following steps:
(1) 3-(1- dimethylaminoethyl is taken) appropriate phenol with mobile phase dissolved dilution is configured to every 1mL diformazan containing 3-(1- ammonia
Base ethyl) phenol 0.1~1 .0mg sample solution；
(2) setting flow rate of mobile phase is 0.8 ~ 1.5ml/min, and Detection wavelength is 210 ~ 240 nm, column temperature: 20 ~ 30 DEG C；
(3) take 10 μ l of sample solution in (1) to inject liquid chromatograph, complete 3-(1- dimethylaminoethyl) phenol and its have
Close the separation and measurement of substance.
9. method for separating and analyzing according to claim 8, Detection wavelength preferably 218 nm described in step 2.
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| CN201710831690.9A CN109507344A (en) | 2017-09-15 | 2017-09-15 | Rivastigmine intermediate and its method for separating and detecting in relation to substance |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104133009A (en) * | 2014-06-30 | 2014-11-05 | 北京万全德众医药生物技术有限公司 | Method using liquid chromatographic method for analysis of rivastigmine hydrogen tartrate related substances |
| CN105116062A (en) * | 2015-06-27 | 2015-12-02 | 万特制药(海南)有限公司 | Method for separation determination of impurity content in rivastigmine tartrate |
-
2017
- 2017-09-15 CN CN201710831690.9A patent/CN109507344A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104133009A (en) * | 2014-06-30 | 2014-11-05 | 北京万全德众医药生物技术有限公司 | Method using liquid chromatographic method for analysis of rivastigmine hydrogen tartrate related substances |
| CN105116062A (en) * | 2015-06-27 | 2015-12-02 | 万特制药(海南)有限公司 | Method for separation determination of impurity content in rivastigmine tartrate |
Non-Patent Citations (2)
| Title |
|---|
| 刘艳玲等: "反相HPLC法测定重酒石酸卡巴拉汀胶囊的含量及有关物质", 《药物分析杂志》 * |
| 王芳侠等: "HPLC法测定重酒石酸卡巴拉汀片含量", 《中国新药杂志》 * |
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