CN109212045A - The method of separating and assaying of escitalopram oxalate residual solvent and impurity - Google Patents
The method of separating and assaying of escitalopram oxalate residual solvent and impurity Download PDFInfo
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Abstract
The invention belongs to analytical chemistry fields, the invention discloses a kind of with residual organic solvent tetrahydrofuran in gas chromatography quick separating detection escitalopram oxalate synthesis technology, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and reaction mass N, the method of N- dimethylamino chloropropane hydrochloride, this method uses polyethylene glycols polarity capillary chromatographic column, flame ionization ditector, tetrahydrofuran in escitalopram oxalate can be quantitative determined, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N, the content of N- dimethylamino chloropropane hydrochloride, to reach effective control to escitalopram oxalate purity, realize the quality controllable of escitalopram oxalate.The method of the present invention specificity is strong, and accuracy is high, and durability is good, and simple and quick.
Description
Technical field
The invention belongs to analytical chemistry fields, and in particular to gas chromatography separation determination escitalopram oxalate residual
Organic solvent tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and impurity N, N- dimethylamino chloropropane hydrochloric acid
The method of salt.
Background technique
Escitalopram oxalate is a kind of terrified barrier treated depressive disorder, treat with or without agoraphobia
Hinder.Escitalopram oxalate chemical name are as follows: 4- [4- (-)-dimethyl amino-1- (4-fluorinated phenyl)-
1-hydroxy butyl]-3-hydroxy methyl benzene nitriles D-(+)-2p-toluene formyl
Tartaric acid salt (2:1)-DTTA salts (D), molecular formula C20H23FN2O2·1/2 C20H18 O8, structural formula
Are as follows:
。
In process of production, the organic solvent and reaction mass used cannot completely remove drug in process, to guarantee drug
Quality and safety, drug is in the requirements for pharmaceuticals declared of registration to organic solvent used in its technical process and reaction mass
Carry out research and effectively control.Organic solvent used in synthesis of oxalic acid escitalopram technique have tetrahydrofuran, isopropyl ether,
Ethyl acetate, isopropanol, acetone and acetic acid, reaction mass have a N, N- dimethylamino chloropropane hydrochloride, wherein N, N- diformazan ammonia
Base chloropropane hydrochloride molecular formula is C5H13Cl2N, structural formula are as follows:
。
Suitable analysis method is selected, accurately organic solvent tetrahydrofuran, isopropyl in separation determination escitalopram oxalate
Ether, ethyl acetate, isopropanol, acetone, acetic acid and reaction mass N, N- dimethylamino chloropropane hydrochloride, to raising oxalic acid Chinese mugwort department
Citalopram quality guarantees that drug safety has great importance.
Summary of the invention
It is organic the purpose of the present invention is to provide being introduced in a kind of separation, detection synthesis of oxalic acid escitalopram technique
Solvents tetrahydrofurane, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and reaction mass N, N- dimethylamino chloropropane hydrochloric acid
The method of salt guarantees escitalopram oxalate to reach effective control to escitalopram oxalate purity and quality
Quality and drug safety.
It is of the present invention it is a kind of separation, measurement escitalopram oxalate residual organic solvent and reaction mass method, be
Using gas chromatographic analysis technique, suitable solvent is selected to dissolve sample, according to the formation and physic-chemical property of substance to be analyzed,
Select polyethylene glycols chromatographic column and flame ionization ditector.
The solvent of above-mentioned described sample dissolution can be in ethyl alcohol, methanol, n,N-Dimethylformamide or dimethyl sulfoxide
It is one or more of.
Above-mentioned described chromatographic column is selected from the brands such as Agilent, Supelco, Phenomenex or Restek.
Above-mentioned described chromatographic column is middle polarity or the polysiloxane-based capillary chromatographic column of polarity.
Method of separating and assaying of the present invention can be realized in accordance with the following methods:
1) it takes escitalopram oxalate appropriate, peak dissolution in dimethyl Asia is added to be made in every 1ml containing escitalopram oxalate
The solution of 100mg, as test solution；Separately take tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N-
Dimethylamino chloropropane hydrochloride is appropriate, and peak dissolution in dimethyl Asia is added to be made in every 1ml containing 72 μ g of tetrahydrofuran, 100 μ of isopropyl ether
G, 500 μ g of ethyl acetate, 500 μ g of isopropanol, 500 μ g of acetone, 500 μ g of acetic acid, N, 500 μ g of N- dimethylamino chloropropane hydrochloride
Solution, as reference substance solution.
2) setting injector temperature is 250 ~ 300 DEG C, and flow rate of carrier gas is 0.8 ~ 1.2mL/min, and programmed temperature method, temperature program is
50 °C of initial temperature, 3 ~ 5min of constant temperature, with 10 ~ 30 °C of heating rate per minute to 220 °C, 5 ~ 10min of constant temperature, detector temperature
Degree is 250 ~ 300 DEG C, and split ratio is 10:1 ~ 50:1.
3) each 0.8~3 μ L of test solution and control solution in 1) is taken, by chromatographic condition 2), gas chromatograph is injected, adopts
With tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N- in external standard method calculating oxalate escitalopram
The content of dimethylamino chloropropane hydrochloride.Wherein:
The model of gas chromatograph, has no special requirements, and the gas chromatograph that the present invention uses is Shimadzu (2010 plus) gas phase color
Spectrometer；
Detector: flame ionization ditector；
Chromatographic column: HP-FFAP capillary chromatographic column (30m*0.32mm, 1.50 μm)；
Injector temperature: 200 DEG C；
Detector temperature: 280 DEG C；
Carrier gas (nitrogen) flow velocity: 1.0mL/min；
Split ratio: 20:1；
Sampling volume: 1 μ L；
Column temperature rise program:
；
The present invention uses gas chromatography, selects polyethylene glycols polarity capillary chromatographic column (30m*0.32mm, 1.50 μm), energy
Fast and effeciently tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, second in separation determination escitalopram oxalate
Acid, N, N- dimethylamino chloropropane hydrochloride solve residual organic solvent tetrahydro in synthesis of oxalic acid escitalopram technique
The separation of furans, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and reaction mass N, N- dimethylamino chloropropane hydrochloride
Measurement problem, to reach effective control to escitalopram oxalate purity.The results are shown in attached figure 1 ~ and 6.
Detailed description of the invention:
The gas chromatogram of solvent (dimethyl Asia peak) when Fig. 1 is embodiment 1；
The gas chromatogram of escitalopram oxalate when Fig. 2 is embodiment 1；
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N when Fig. 3 is embodiment 1, N- dimethylamino chlorine third
The gas chromatogram of heptane hydrochloride salt；
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N- dimethylamino are added when Fig. 4 is embodiment 1
The escitalopram oxalate sample gas chromatogram of chloropropane hydrochloride；
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N when Fig. 5 is embodiment 2, N- dimethylamino chlorine third
The gas chromatogram of heptane hydrochloride salt；
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N when Fig. 6 is embodiment 3, N- dimethylamino chlorine third
The gas chromatogram of heptane hydrochloride salt.
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 residual organic solvent tetrahydrofuran in the escitalopram oxalate that is related to, isopropyl ether, ethyl acetate, isopropanol, acetone,
Acetic acid and reaction mass N, N- dimethylamino chloropropane hydrochloride detection method are described in further detail, but should not manage this
Solution is only limitted to example below for the range of the above-mentioned theme of the present invention, and all technologies realized based on above content of the present invention are belonged to
In the scope of the present invention.
Embodiment 1:
Instrument and condition:
Chromatograph: 2010 plus gas chromatograph of Shimadzu；
Detector: flame ionization ditector；
Chromatographic column: HP-FFAP capillary chromatographic column (30m*0.32mm, 1.50 μm)；
Injector temperature: 200 DEG C；
Detector temperature: 280 DEG C；
Carrier gas (nitrogen) flow velocity: 1.0mL/min；
Split ratio: 20:1；
Sampling volume: 1 μ L；
Column temperature rise program:
。
Experimental procedure:
It takes escitalopram oxalate appropriate, adds peak dissolution in dimethyl Asia that 100mg containing escitalopram oxalate in every 1ml is made
Solution, as escitalopram oxalate sample solution；Take tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, second
Acid, N, N- dimethylamino chloropropane hydrochloride is appropriate, and peak dissolution in dimethyl Asia is added to be made in every 1ml containing 72 μ g of tetrahydrofuran, different
100 μ g of propyl ether, 500 μ g of ethyl acetate, 500 μ g of isopropanol, 500 μ g of acetone, 500 μ g of acetic acid, N, N- dimethylamino chloropropane salt
The solution of 500 μ g of hydrochlorate, as reference substance solution；Separately take dimethyl Asia peak as blank solution.It is carried out by above-mentioned chromatographic condition
Analysis records chromatogram, by external standard method with tetrahydrofuran, isopropyl ether, acetic acid second in calculated by peak area escitalopram oxalate
Ester, isopropanol, acetone, acetic acid, N, the content of N- dimethylamino chloropropane hydrochloride.The results are shown in attached figure 1 ~ 4, Fig. 1 be blank it is molten
Liquid chromatography figure；Fig. 2 is escitalopram oxalate sample solution chromatogram.The chromatographic peak of retention time 12.436min is in Fig. 3
Tetrahydrofuran, the chromatographic peak of retention time 9.762min are isopropyl ether, and the chromatographic peak of retention time 12.709min is acetic acid second
Ester, the chromatographic peak of retention time 13.299min are isopropanol, and the chromatographic peak of retention time 11.607min is acetone, retention time
The chromatographic peak of 23.227min is acetic acid, and the chromatographic peak of retention time 17.848min is N, N- dimethylamino chloropropane hydrochloride.
Fig. 4 is that tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N is added, N- dimethylamino chloropropane hydrochloride
Escitalopram oxalate sample gas chromatogram.Fig. 1 ~ Fig. 4 shows: method provided by the invention can fast and effeciently separate survey
Determine tetrahydrofuran in escitalopram oxalate, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N- dimethylamino chlorine
Propane hydrochloride salt, and can accurately carry out quantitative detection, to reach to the effective of escitalopram oxalate purity and quality
Control.
Embodiment 2:
Instrument and condition:
Chromatograph: 2010 plus gas chromatograph of Shimadzu；
Detector: flame ionization ditector；
Chromatographic column: HP-FFAP capillary chromatographic column (30m*0.32mm, 1.50 μm)；
Injector temperature: 210 DEG C；
Detector temperature: 260 DEG C；
Carrier gas (nitrogen) flow velocity: 1.0mL/min；
Split ratio: 50:1；
Sampling volume: 1 μ L；
Column temperature rise program:
。
Experimental procedure:
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N are taken, N- dimethylamino chloropropane hydrochloride is appropriate,
Add peak dissolution in dimethyl Asia to be made in every 1ml and contains 72 μ g of tetrahydrofuran, 100 μ g of isopropyl ether, 500 μ g of ethyl acetate, isopropanol
500 μ g, 500 μ g of acetone, 500 μ g of acetic acid, N, the solution of 500 μ g of N- dimethylamino chloropropane hydrochloride, as reference substance solution；
Separately take dimethyl Asia peak as blank solution.It is analyzed by above-mentioned chromatographic condition, records chromatogram.The results are shown in attached figure 5, Fig. 5
The chromatographic peak of middle retention time 12.497min is tetrahydrofuran, and the chromatographic peak of retention time 9.828min is isopropyl ether, when reservation
Between the chromatographic peak of 12.769min be ethyl acetate, the chromatographic peak of retention time 13.358min is isopropanol, retention time
The chromatographic peak of 11.668min is acetone, and the chromatographic peak of retention time 23.272min is acetic acid, the color of retention time 17.942min
Spectral peak is N, N- dimethylamino chloropropane hydrochloride.
Embodiment 3:
Instrument and condition:
Chromatograph: 2010 plus gas chromatograph of Shimadzu；
Detector: flame ionization ditector；
Chromatographic column: HP-FFAP capillary chromatographic column (30m*0.32mm, 1.50 μm)；
Injector temperature: 220 DEG C；
Detector temperature: 300 DEG C；
Carrier gas (nitrogen) flow velocity: 1.1mL/min；
Split ratio: 20:1；
Sampling volume: 1 μ L
Column temperature rise program:
。
Experimental procedure:
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N are taken, N- dimethylamino chloropropane hydrochloride is appropriate,
Add peak dissolution in dimethyl Asia to be made in every 1ml and contains 72 μ g of tetrahydrofuran, 100 μ g of isopropyl ether, 500 μ g of ethyl acetate, isopropanol
500 μ g, 500 μ g of acetone, 500 μ g of acetic acid, N, the solution of 500 μ g of N- dimethylamino chloropropane hydrochloride, as reference substance solution；
Separately take dimethyl Asia peak as blank solution.It is analyzed by above-mentioned chromatographic condition, records chromatogram.The results are shown in attached figure 6, Fig. 6
The chromatographic peak of middle retention time 11.318min is tetrahydrofuran, and the chromatographic peak of retention time 8.686min is isopropyl ether, when reservation
Between the chromatographic peak of 11.612min be ethyl acetate, the chromatographic peak of retention time 12.218min is isopropanol, retention time
The chromatographic peak of 10.498min is acetone, and the chromatographic peak of retention time 22.218min is acetic acid, the color of retention time 16.890min
Spectral peak is N, N- dimethylamino chloropropane hydrochloride.
The present invention to tetrahydrofuran in the escitalopram oxalate, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid,
The following items of N, N- dimethylamino chloropropane hydrochloride analysis method are verified:
System suitability experiment:
Take escitalopram oxalate and tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N- diformazan ammonia
Base chloropropane hydrochloride is appropriate, with dimethyl Asia peak sample dissolution, is configured to containing escitalopram oxalate and tetrahydrofuran, different
Propyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, the system suitability of N- dimethylamino chloropropane hydrochloride.By embodiment 1
Chromatographic condition carry out gas chromatographic analysis, record chromatogram.By Fig. 1 ~ Fig. 4 it is found that tetrahydrofuran, isopropyl with this condition
Ether, ethyl acetate, isopropanol, acetone, acetic acid, N, separating degree is good between N- dimethylamino chloropropane hydrochloride and adjacent peak,
In solvent and escitalopram oxalate other impurities do not interfere tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone,
Acetic acid, N, the measurement of N- dimethylamino chloropropane hydrochloride.
Sample introduction repetitive test:
By tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N, the control of N- dimethylamino chloropropane hydrochloride
Product solution is repeated sample introduction 6 times by the chromatographic condition of embodiment 1, is investigated the repeatability of method, as a result see the table below.It can by result
Add, this method sample introduction repeatability is good.
。
Quantitative limit, detection limit:
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N are taken, N- dimethylamino chloropropane hydrochloride is suitable
Amount, it is accurately weighed, dimethyl Asia peak sample dissolution is used respectively, is configured to the reference substance solution of response, then accurate measurement reference substance
Appropriate solution dilutes step by step, investigates by the chromatographic condition sample introduction of embodiment 1.Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropyl
Alcohol, acetone, acetic acid, N, N- dimethylamino chloropropane hydrochloride quantitative limit and detection limit data are as shown in the table:
。
It is linear:
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N are taken, N- dimethylamino chloropropane hydrochloride is suitable
Amount, it is accurately weighed, respectively with dimethyl Asia peak dissolve, be configured to tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone,
Acetic acid, N, N- dimethylamino chloropropane hydrochloride stock solution；Precision measure tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol,
Acetone, acetic acid, N, N- dimethylamino chloropropane hydrochloride stock solution are diluted to quantitative limit concentration, 50%, 100%, 120% and respectively
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, the N of 150% limit concentration, N- dimethylamino chloropropane salt
Each solution is investigated by the chromatographic condition sample introduction of embodiment 1, as a result be see the table below by hydrochlorate reference substance solution:
。
Accuracy:
Tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N are taken, N- dimethylamino chloropropane hydrochloride is suitable
Amount, accurately weighed, with dimethyl Asia peak dissolved dilution, the accuracy test for being made into 80%, 100% and 120% limit concentration respectively is molten
Liquid.Escitalopram oxalate about 100mg is taken, respectively with the accuracy test solution of the limit concentration of above-mentioned 80%, 100% and 120%
1mL dissolution, as 80%, 100% and 120% test solution, each concentration level test solution prepares 3 parts in parallel；Separately take oxalic acid
The dissolution of 1mL dimethyl Asia peak is added, as sample solution in escitalopram about 100mg.By above-mentioned solution by embodiment 1
Chromatographic condition sample introduction investigate, Fig. 4 be 100% test solution (i.e. in escitalopram oxalate be added tetrahydrofuran, isopropyl ether,
Ethyl acetate, isopropanol, acetone, acetic acid, N, N- dimethylamino chloropropane hydrochloride) chromatogram, retention time is
The chromatographic peak of 12.436min is tetrahydrofuran, and the chromatographic peak that retention time is 9.762min is isopropyl ether, and retention time is
The chromatographic peak of 12.709min is ethyl acetate, and the chromatographic peak that retention time is 13.299min is isopropanol, and retention time is
The chromatographic peak of 11.607min is acetone, and the chromatographic peak that retention time is 23.227min is acetic acid, retention time 17.848min
Chromatographic peak be N, N- dimethylamino chloropropane hydrochloride, sample introduction result see the table below:
；
；
。
Durability:
By chromatographic conditions such as fine tuning injector temperature, flow rate of carrier gas, detector temperature and chromatographic column brands, we are further examined
The durability of method is examined.As a result, it has been found that this method changes the chromatographic column of different brands, injector temperature, flow rate of carrier gas becomes
Good tolerance under the conditions of change, detector temperature variation etc..In different brands chromatographic column, different injector temperatures, flow rate of carrier gas
And under the conditions of detector temperature, tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid, N, N- dimethylamino chlorine third
Heptane hydrochloride salt retention time can reach and efficiently separate without significant changes.
Claims (7)
1. a kind of utilize residual organic solvent tetrahydro furan in gas chromatography separation detection escitalopram oxalate synthesis technology
It mutters, the method for isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and reaction mass N, N- dimethylamino chloropropane hydrochloride,
It is characterized by: select suitable solvent by escitalopram oxalate and tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol,
Acetone, acetic acid, N, the dissolution of N- dimethylamino chloropropane hydrochloride select polyethylene glycols capillary chromatography with gas chromatography
Column and flame ionization ditector realize separation detection.
2. method of separating and assaying according to claim 1, suitable solvent can be ethyl alcohol, methanol, N, N- dimethyl methyl
One or more of amide or dimethyl sulfoxide.
3. method of separating and assaying according to claim 1, chromatographic column be selected from brand be Agilent, Supelco,
The chromatographic column of Phenomenex or Restek.
4. method of separating and assaying according to claim 1, chromatographic column is middle polarity or polarity polyethylene glycols capillary
Chromatographic column.
5. method of separating and assaying according to claim 1, which is characterized in that including the following steps:
It takes escitalopram oxalate appropriate, adds peak dissolution in dimethyl Asia that 100mg containing escitalopram oxalate in every 1ml is made
Solution, as test solution；Separately take tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N, N- diformazan
Amino chloropropane hydrochloride is appropriate, and peak dissolution in dimethyl Asia is added to be made in every 1ml containing 72 μ g of tetrahydrofuran, 100 μ g of isopropyl ether, second
500 μ g of acetoacetic ester, 500 μ g of isopropanol, 500 μ g of acetone, 500 μ g of acetic acid, N, 500 μ g's of N- dimethylamino chloropropane hydrochloride is molten
Liquid, as reference substance solution；
2) setting injector temperature is 150 ~ 250 DEG C, and flow rate of carrier gas is 0.8 ~ 1.2mL/min, and programmed temperature method, temperature program is
50 °C of initial temperature, 3 ~ 5min of constant temperature, with 10 ~ 30 °C of heating rate per minute to 220 °C, 5 ~ 10min of constant temperature, detector temperature
Degree is 250 ~ 300 DEG C, and split ratio is 10:1 ~ 50:1；
3) each 0.8~3 μ L of test solution and control solution in 1) is taken, by chromatographic condition 2), gas chromatograph is injected, adopts
With tetrahydrofuran, isopropyl ether, ethyl acetate, isopropanol, acetone, acetic acid and N, N- in external standard method calculating oxalate escitalopram
The content of dimethylamino chloropropane hydrochloride.
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:
It is 50 °C of initial temperature, constant temperature 5min, with 10 °C of heating rate per minute to 220 °C, constant temperature 10min.
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| CN110873761A (en) * | 2018-09-03 | 2020-03-10 | 万全万特制药江苏有限公司 | Gas chromatography detection method for escitalopram oxalate intermediate related substances |
| CN111650289A (en) * | 2020-04-16 | 2020-09-11 | 江苏艾立康药业股份有限公司 | Method for determining related substances of 3-chloro-1- (N, N-dimethyl) propylamine hydrochloride |
| CN112903861A (en) * | 2021-01-26 | 2021-06-04 | 山东省药学科学院 | Method for detecting residual solvent in dextro-rabeprazole sodium raw material medicine |
| CN112903861B (en) * | 2021-01-26 | 2022-11-15 | 山东省药学科学院 | Method for detecting residual solvent in dextral rabeprazole sodium bulk drug |
| CN114924000A (en) * | 2022-05-12 | 2022-08-19 | 陕煤集团榆林化学有限责任公司 | Method for detecting content of diisopropyl ether in crude phenol |
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