CN106501386A - A kind of method of diethanol amine content in use gas chromatography separation determination Aripiprazole - Google Patents
A kind of method of diethanol amine content in use gas chromatography separation determination Aripiprazole Download PDFInfo
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- CN106501386A CN106501386A CN201610836192.9A CN201610836192A CN106501386A CN 106501386 A CN106501386 A CN 106501386A CN 201610836192 A CN201610836192 A CN 201610836192A CN 106501386 A CN106501386 A CN 106501386A
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- aripiprazole
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- 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 field, the invention discloses a kind of method of the relevant material diethanol amine of use gas chromatography quick separating detection Aripiprazole, the method adopts methyl polysiloxane class low pole capillary chromatographic column, flame ionization ditector, the content of diethanol amine in Aripiprazole can be quantitative determined, so as to reach the effective control to Aripiprazole purity, the quality controllable of Aripiprazole is realized.The inventive method specificity is strong, and the degree of accuracy is high, and durability is good, and simple to operate quick.
Description
Technical field
The invention belongs to analytical chemistry field, and in particular in gas chromatography separation determination Aripiprazole, diethanol amine contains
The method of amount.
Background technology
Aripiprazole system quinoline ketone derivative, is first third generation atypical antipsychotic new drug, can nerveous system to DA
System has dual regulation, is the stabilizer of DA mediators.Aripiprazole has very high with D2, D3,5-HT1A and 5-HT2A acceptor
Affinity.Anti- essence is produced by the effect of partial agonist to D2 and 5-HT1A acceptors and to the antagonism of 5-HT2A acceptors
Refreshing Split disease effect.Clinic cures mainly various acute and chronic schizophrenia and the disturbance of emotion.Entitled 7- { the 4- of Aripiprazole chemistry
[4- (2,3- dichlorophenyl)-l- piperazinyls] butoxy } -2 (1H)-quinolinone of -3,4- dihydros, molecular formula is C23H27N3O2Cl2,
Structural formula is：
.
The bad reaction that medicine is produced in Clinical practice except relevant with the pharmacologically active of medicine itself, sometimes with medicine
Present in impurity also have much relations, be therefore directly connected to the quality and security of medicine to the effective control of impurity.
The organic impurities introduced in synthesis Aripiprazole technique has diethanol amine, and its structural formula is：
.
Select suitable analysis method, exactly separate and determine Aripiprazole in diethanol amine content, to improve Ah
Vertical piperazine azoles quality, ensure that drug safety is significant.
Content of the invention
It is an object of the invention to provide the organic impurities diethyl introduced in a kind of separation detection Aripiprazole technical process
The method of alcohol amine content, so that reach the effective control to Aripiprazole purity and quality, it is ensured that the quality and use of Aripiprazole
Medicine security.
The method of diethanol amine content in a kind of separation determination Aripiprazole of the present invention, is using gas-chromatography point
Sample is dissolved by analysis technology from suitable solvent, according to the formation and physic-chemical property of impurity to be analyzed, from suitable polarity
Polysiloxane-based capillary chromatographic column and detector.
Above-mentioned described solvent can be the one kind or several in methyl alcohol, ethanol, dichloromethane or DMF
Kind.
Above-mentioned described chromatographic column is selected from brands such as Agilent, Supelco, Phenomenex or Restek.
Above-mentioned described chromatographic column is low pole or the polysiloxane-based capillary chromatographic column of middle grade.
Above-mentioned described detector is flame ionization ditector.
Method of separating and assaying of the present invention, can be realized in accordance with the following methods：
1）Take Aripiprazole in right amount, the solution in every 1ml containing Aripiprazole 100mg is made in the dissolving that adds methylene chloride, as confession examination
Product solution；Diethanol amine is separately taken in right amount, and the solution in every 1ml containing diethanol amine 0.1mg is made in the dissolving that adds methylene chloride, used as right
According to product solution；
2）It is 200 ~ 250 DEG C to arrange injector temperature, and flow rate of carrier gas is 0.8 ~ 1.2mL/min, programmed temperature method, and heating schedule is
50 °C of initial temperature, maintains 2 ~ 5min, with 10 ~ 25 °C per minute of heating rate to 220 °C, 2 ~ 5min of constant temperature, and detector temperature
Spend for 250 ~ 300 DEG C, split ratio is 10:1~50:1；
3）Take 1）Middle need testing solution and each 0.8～3 μ L of reference substance solution, by 2）Chromatographic condition, inject gas chromatograph, adopt
The content that diethanol amine in Aripiprazole is calculated with external standard method.
Wherein：
The model of gas chromatograph, has no special requirements, and the gas chromatograph that the present invention is adopted is for Agilent 6890N gas-chromatographies
Instrument
Detector：Flame ionization ditector；
Chromatographic column：8 CB capillary chromatographic columns of CP-Sil（30m*0.32mm, 1.00 μm）；
Injector temperature：200℃；
Detector temperature：280℃；
Carrier gas（Nitrogen）Flow velocity：1.0mL/min；
Split ratio：20:1；
Sampling volume：1μL
Column temperature rise program：
| Heating rate（℃/min） | Temperature（℃） | Retention time（min） |
| / | 50 | 3 |
| 20 | 220 | 3 |
.The present invention adopts gas chromatography, from methyl polysiloxane class low pole capillary chromatographic column（30m*0.32mm,
1.00μm）, can fast and effeciently in separation determination Aripiprazole diethanol amine content, solve in Aripiprazole technical process
The separation determination of the organic impurities diethanol amine of introducing, so that reach the effective control to Aripiprazole purity, it is ensured that A Li piperazines
The quality of azoles and drug safety.As a result see accompanying drawing 1 ~ 5.
Description of the drawings
Solvent when Fig. 1 is embodiment 1（Dichloromethane）Gas chromatogram；
The gas chromatogram of Aripiprazole blank sample when Fig. 2 is embodiment 1；
The gas chromatogram of diethanol amine when Fig. 3 is embodiment 1；
The gas chromatogram of diethanol amine when Fig. 4 is embodiment 2；
The gas chromatogram of diethanol amine when Fig. 5 is embodiment 3；
When Fig. 6 is embodiment 1, Aripiprazole contains the gas chromatogram of diethanol amine.
Specific embodiment：
Following examples are used for further understanding the present invention, but are not limited to the scope of this enforcement.Below by way of example forms, to this
In the Aripiprazole that invention is related to, diethanol amine detection method is described in further detail, but this should not be interpreted as the present invention
The scope of above-mentioned theme is only limitted to Examples below, and all technology that is realized based on the above of the present invention belong to the present invention's
Scope.
Embodiment 1
Instrument and condition
Chromatograph：Agilent 6890N gas chromatographs；
Detector：Flame ionization ditector；
Chromatographic column：8 CB capillary chromatographic columns of CP-Sil（30m*0.32mm, 1.00 μm）；
Injector temperature：200℃；
Detector temperature：280℃；
Carrier gas（Nitrogen）Flow velocity：1.0mL/min；
Split ratio：20:1；
Sampling volume：1μL
Column temperature rise program：
| Heating rate（℃/min） | Temperature（℃） | Retention time（min） |
| / | 50 | 3 |
| 20 | 220 | 3 |
Experimental procedure
Take Aripiprazole in right amount, the solution in every 1ml containing Aripiprazole 100mg is made in the dissolving that adds methylene chloride, used as A Li piperazines
Azoles sample solution；Take diethanol amine in right amount, the solution in every 1ml containing diethanol amine 0.1mg is made in the dissolving that adds methylene chloride, and makees
For reference substance solution；Dichloromethane is separately taken as blank solution.It is analyzed by above-mentioned chromatographic condition, records chromatogram, by outer
Mark method is with the content of diethanol amine in calculated by peak area Aripiprazole.As a result see accompanying drawing 1 ~ 3, Fig. 1 is blank solution chromatogram；Figure
2 is Aripiprazole sample solution chromatogram.In Fig. 3, the chromatographic peak of retention time 10.817min is diethanol amine.Fig. 1 ~ Fig. 3 tables
Bright：The method that the present invention is provided can fast and effeciently in separation determination Aripiprazole diethanol amine content, it is possible to accurately enter
Row quantitative determination, so that reach the effective control to Aripiprazole purity and quality.
Embodiment 2
Instrument and condition
Chromatograph：Agilent 6890N gas chromatographs；
Detector：Flame ionization ditector；
Chromatographic column：8 CB capillary chromatographic columns of CP-Sil（30m*0.32mm, 1.00 μm）；
Injector temperature：200℃；
Detector temperature：280℃；
Carrier gas（Nitrogen）Flow velocity：0.9mL/min；
Split ratio：20:1；
Sampling volume：1μL
Column temperature rise program：
| Heating rate（℃/min） | Temperature（℃） | Retention time（min） |
| / | 50 | 3 |
| 20 | 220 | 3 |
Experimental procedure
Take diethanol amine in right amount, the solution containing diethanol amine 0.1mg in every 1ml is made in the dissolving that adds methylene chloride, used as control
Product solution；Dichloromethane is separately taken as blank solution.It is analyzed by above-mentioned chromatographic condition, records chromatogram.As a result see accompanying drawing
In 4, Fig. 4, the chromatographic peak of retention time 11.119min is diethanol amine.
Embodiment 3
Instrument and condition
Chromatograph：Agilent 6890N gas chromatographs；
Detector：Flame ionization ditector；
Chromatographic column：8 CB capillary chromatographic columns of CP-Sil（30m*0.32mm, 1.00 μm）；
Injector temperature：195℃；
Detector temperature：280℃；
Carrier gas（Nitrogen）Flow velocity：1.0mL/min；
Split ratio：20:1；
Sampling volume：1μL
Column temperature rise program：
| Heating rate（℃/min） | Temperature（℃） | Retention time（min） |
| / | 50 | 3 |
| 20 | 220 | 3 |
Experimental procedure
Take diethanol amine in right amount, the solution containing diethanol amine 0.1mg in every 1ml is made in the dissolving that adds methylene chloride, used as control
Product solution；Dichloromethane is separately taken as blank solution.It is analyzed by above-mentioned chromatographic condition, records chromatogram.As a result see accompanying drawing
In 5, Fig. 5, the chromatographic peak of retention time 10.831min is diethanol amine.
The present invention is verified to the following items of diethanol amine analysis method in the Aripiprazole：
System suitability is tested
Aripiprazole and appropriate diethanol amine is taken, dichloromethane sample dissolution is used respectively, is configured to containing Aripiprazole and diethanol
The test liquid of amine.Gas chromatographic analysis is carried out by the chromatographic condition of embodiment 1, chromatogram is recorded.From Fig. 1 ~ Fig. 6, here
Under the conditions of between diethanol amine and adjacent peak, separating degree is good, solvent and Aripiprazole other impurities do not disturb diethanol amine
Determine.
Sample introduction replica test
By the relevant material diethanol amine test liquid of Aripiprazole, by the chromatographic condition of embodiment 1, repeat sample introduction 6 times, investigation side
The repeatability of method.Can be added by result, the method sample introduction repeatability is good：
| Number of injections | 1 | 2 | 3 | 4 | 5 | 6 | Mean value | RSD% |
| Diethanol amine (A) | 20.1 | 19.8 | 19.9 | 19.9 | 21.2 | 21.4 | 20.4 | 3.53 |
Quantitative limit, test limit
The relevant material diethanol amine for taking Aripiprazole is appropriate, accurately weighed, uses dichloromethane sample dissolution respectively, is configured to ring
The test liquid that answers, then precision measures that test liquid is appropriate, stepwise dilution is investigated by the chromatographic condition sample introduction of embodiment 1.Diethanol amine
Quantitative limit and test limit data are as shown in the table：
| Project | Diethanol amine |
| Quantitative limit（ng/μL） | 18.46 |
| Test limit (ng/ μ L) | 9.28 |
Linearly
The relevant material diethanol amine for taking Aripiprazole is appropriate, accurately weighed, is dissolved with dichloromethane respectively, is configured to diethanol
Amine stock solution；Precision measures diethanol amine stock solution, is diluted to 20% respectively（Quantitative limit concentration）, 50%, 80%, 100% and 120%
The diethanol amine need testing solution of limit concentration, each solution is investigated by the chromatographic condition sample introduction of embodiment 1, as a result be see the table below：
The degree of accuracy
The relevant material diethanol amine for taking Aripiprazole is appropriate, accurately weighed, is dissolved with dichloromethane respectively, is configured to diethanol
Amine stock solution；Precision measures diethanol amine stock solution in right amount, with dchloromethane, is made into 80%, 100% and 120% limit respectively
The accuracy test solution of concentration.Aripiprazole about 100mg is taken, accurate with the limit concentration of above-mentioned 80%, 100% and 120% respectively
The 1mL dissolvings of degree testing liquid, used as 80%, 100% and 120% need testing solution, each concentration level need testing solution is parallel to prepare 3
Part；Aripiprazole about 100mg is separately taken, the dissolving of 1mL dichloromethane is added, as blank sample solution.By above-mentioned solution by enforcement
The chromatographic condition sample introduction of example 1 is investigated, and Fig. 6 is 100% need testing solution（Diethanol amine is added i.e. in Aripiprazole）Chromatogram,
Retention time is diethanol amine for the chromatographic peak of 10.818min, and sample introduction result see the table below：
Durability
By finely tuning injector temperature, flow rate of carrier gas, detector temperature and chromatographic column brand isochromatic spectrum condition, we further examine
The durability of method is examined.As a result find, chromatographic column, injector temperature change ± 5 DEG C, carrier gas stream of the method to different brands
Good tolerance under the conditions of speed change ± 0.1mL/min, ± 5 DEG C of detector temperature change etc..In different brands chromatographic column, difference
Under the conditions of injector temperature, flow rate of carrier gas and detector temperature, diethanol amine retention time is without significant changes, and can reach and have
Effect is separated.
Claims (8)
1. method of a kind of utilization gas chromatography separation detection Aripiprazole about material diethanol amine, it is characterised in that：Choosing
Sample and diethanol amine are dissolved with suitable solvent, according to the formation and physic-chemical property of impurity to be analyzed, from suitable polarity
Polysiloxane-based capillary chromatographic column and detector.
2. method of separating and assaying according to claim 1, solvent can be methyl alcohol, ethanol, dichloromethane or N, N- diformazan
One or more in base formamide.
3. method of separating and assaying according to claim 1, chromatographic column 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 are low pole or the polysiloxane-based capillary of middle grade
Pipe chromatographic column.
5. method of separating and assaying according to claim 1, detector select flame ionization ditector（FID）.
6. method of separating and assaying according to claim 1, it is characterised in that including following step：
1）Take Aripiprazole in right amount, the solution in every 1ml containing Aripiprazole 100mg is made in the dissolving that adds methylene chloride, as confession examination
Product solution；Diethanol amine is separately taken in right amount, and the solution in every 1ml containing diethanol amine 0.1mg is made in the dissolving that adds methylene chloride, as
Reference substance solution；
2）Arrange injector temperature be 200 ~ 250 DEG C, flow rate of carrier gas be 0.8 ~ 1.2mL/min, programmed temperature method, heating schedule
For 50 °C of initial temperature, 2 ~ 5min is maintained, with 10 ~ 25 °C per minute of heating rate to 220 °C, 2 ~ 5min of constant temperature, detector
Temperature is 250 ~ 300 DEG C, and split ratio is 10:1~50:1；
3）Take 1）Middle need testing solution and each 0.8～3 μ L of reference substance solution, by 2）Chromatographic condition, inject gas chromatograph, adopt
The content that diethanol amine is calculated with external standard method.
7. method for separating and analyzing according to claim 6, step 2）Described carrier gas is nitrogen or helium.
8. method for separating and analyzing according to claim 6, step 2）Described programmed temperature method, preferably following intensification journey
Sequence：
.
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| CN201610836192.9A CN106501386A (en) | 2016-09-21 | 2016-09-21 | A kind of method of diethanol amine content in use gas chromatography separation determination Aripiprazole |
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Cited By (3)
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| CN110850012A (en) * | 2018-08-21 | 2020-02-28 | 成都弘达药业有限公司 | Detection method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride and related substances thereof |
| CN113514565A (en) * | 2020-04-10 | 2021-10-19 | 昆药集团股份有限公司 | Detection method of residual ethylenediamine and piperazine in homopiperazine |
| CN115993414A (en) * | 2023-01-18 | 2023-04-21 | 中汽研汽车零部件检验中心(宁波)有限公司 | Method for determining amine substances of automobile nonmetallic material |
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| CN110850012A (en) * | 2018-08-21 | 2020-02-28 | 成都弘达药业有限公司 | Detection method of 1- (2, 3-dichlorophenyl) piperazine hydrochloride and related substances thereof |
| CN113514565A (en) * | 2020-04-10 | 2021-10-19 | 昆药集团股份有限公司 | Detection method of residual ethylenediamine and piperazine in homopiperazine |
| CN115993414A (en) * | 2023-01-18 | 2023-04-21 | 中汽研汽车零部件检验中心(宁波)有限公司 | Method for determining amine substances of automobile nonmetallic material |
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