CN112114051A - Method for detecting genotoxic impurity halogenated alkane in aripiprazole - Google Patents
Method for detecting genotoxic impurity halogenated alkane in aripiprazole Download PDFInfo
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Abstract
The invention relates to the technical field of medicine quality detection, and provides a method for detecting genotoxic impurity halogenated alkane in aripiprazole, which comprises the steps of firstly preparing a test solution of aripiprazole and a reference solution containing 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane, then detecting by using a gas chromatography-mass spectrometry method, and calculating by an external standard method to obtain the content of the 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the aripiprazole. The method provided by the invention has good specificity and durability, can accurately detect each genotoxic impurity in the aripiprazole, and has good separation degree of each peak, good theoretical plate number and tailing factor symmetric factor and high response.
Description
Technical Field
The invention relates to the technical field of medicine quality detection, in particular to a method for detecting genotoxic impurity halogenated alkane in aripiprazole.
Background
Aripiprazole is a novel atypical anti-schizophrenia drug, has bidirectional regulation effect on DA-ergic nervous system, and is a stabilizer of DA transmitter. Has high affinity with D2, D3, 5-HT1A and 5-HT2A receptors, and has anti-schizophrenia effect through partial agonism on D2 and 5-HT1A receptors and antagonism on 5-HT2A receptors.
Compounds formed by partial or complete replacement of hydrogen atoms in alkane molecules by halogen atoms are referred to as haloalkanes, referred to as haloalkanes. The alkyl halide is widely used in a plurality of industries as an important organic solvent and a product intermediate, but is a carcinogenic teratogenic and mutagenic substance, so that the attention of human beings to health is paid more and more, and the control of the organic solvent and the product intermediate is paid more and more. 1-bromo-4-chlorobutane is used as one of the starting materials in the aripiprazole synthesis process, and 1, 4-dichlorobutane and 1, 4-dibromobutane may be contained in the 1-bromo-4-chlorobutane synthesis process, so that the residues of three genotoxic impurities, namely 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane, in the aripiprazole finished product need to be controlled.
Through inquiry, the pharmacopoeia of various countries has no detection method for halogenated hydrocarbon in aripiprazole, the maximum daily dose of aripiprazole is 30mg, the general threshold value specified in the guiding principle of the gene toxic impurity limit is 1.5 mug/day, the limit concentration of the halogenated hydrocarbon is 50ppm through conversion, and the analysis difficulty is large due to the low limit.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for detecting a genotoxic impurity halogenated alkane in aripiprazole, which is rapid and accurate, has a low detection limit, and can effectively control 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane which may be remained in aripiprazole.
In order to achieve the above object, the present invention provides the following technical solutions:
a method for detecting genotoxic impurity halogenated alkane in aripiprazole comprises the following steps:
(1) dissolving aripiprazole in a solvent to obtain a test solution;
(2) dissolving a reference substance of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in a solvent to obtain a reference substance solution;
(3) respectively carrying out gas chromatography-mass spectrometry detection on the test solution and the reference solution to obtain a spectrogram of a solution to be detected and a spectrogram of the reference solution, and calculating by using an external standard method to obtain the contents of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the aripiprazole;
the step (1) and the step (2) have no requirement of time sequence.
Preferably, the solvent in step (1) and step (2) comprises one or more of dichloromethane, chloroform, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
Preferably, the concentration of the aripiprazole in the test solution is 9-11 mg/mL.
Preferably, the concentrations of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the control solution are independently 0.4-0.6. mu.g/mL.
Preferably, the sample volumes of the test solution and the reference solution in the gas chromatography-mass spectrometry detection are both 1 μ L.
Preferably, the gas chromatography-mass spectrometry detection conditions are as follows:
a chromatographic column: a capillary column taking 6% of cyanopropylphenyl-94% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 35% of diphenyl-65% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 5% of diphenyl-95% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 50% of diphenyl-50% of dimethylpolysiloxane as a stationary liquid;
carrier gas: helium gas;
flow rate: 0.9mL/min to 1.1 mL/min;
temperature programming: the initial column temperature of the chromatographic column is 98-102 ℃, the initial column temperature is kept for 5min, the temperature is raised to 150 ℃ at the speed of 5 ℃/min, and the initial column temperature is kept for 2 min;
sample inlet temperature: 180 ℃;
the split ratio is as follows: 11: 1-9: 1.
Preferably, the flow rate is 1.0mL/min, and the split ratio is 10: 1; the initial column temperature of the chromatographic column was 100 ℃.
Preferably, the mass spectrometric conditions for the gas chromatography-mass spectrometric detection are as follows: the temperature of the transmission line is 190-210 ℃, the temperature of the ion source is 220-240 ℃, the temperature of the four-level bar is 140-160 ℃, the detection mode is selected ion monitoring, and the extracted ions are m/z55.00, m/z91.00 and m/z 135.00; residence time was 100ms, solvent delay time was 4min, low resolution mode.
Preferably, the temperature of the transmission line is 200 ℃, the temperature of the ion source is 230 ℃, and the temperature of the quadrupole is 150 ℃.
The invention provides a method for detecting genotoxic impurity halogenated alkane in aripiprazole, which comprises the steps of firstly preparing a test solution of aripiprazole and a reference solution containing 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane, then detecting by using a gas chromatography-mass spectrometry method, and calculating the content of the 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the aripiprazole by an external standard method. The method provided by the invention has good specificity and durability, and the detection of halogenated alkane as the toxic impurity of the aripiprazole gene cannot be influenced by changing chromatographic conditions such as flow rate, initial column temperature, split flow ratio and the like in a small range; the method provided by the invention can accurately detect each genotoxic impurity in aripiprazole, and the separation degree, the number of theoretical plates and the symmetric factor of each peak are good, and the response is high.
Drawings
FIG. 1 is a spectrum of methylene chloride as an empty solvent in example 1;
FIG. 2 is a spectrum of 1, 4-dichlorobutane in example 1;
FIG. 3 is a spectrum of 1-bromo-4-chlorobutane of example 1;
FIG. 4 is a spectrum of 1, 4-dibromobutane of example 1;
FIG. 5 is a spectrum of the control of example 1;
FIG. 6 is a spectrum of aripiprazole of example 1;
FIG. 7 is a graph showing a mixed spectrum of aripiprazole-haloalkane in example 1 and the results thereof;
FIG. 8 is a graph showing a mixed spectrum of aripiprazole and haloalkane at a flow rate of 1.1mL/min in example 2;
FIG. 9 is a graph showing a mixed spectrum of aripiprazole and haloalkane at a flow rate of 0.9mL/min in example 2;
FIG. 10 is a graph showing a mixed spectrum of aripiprazole and haloalkane at an initial column temperature of 98 ℃ in the column of example 2;
FIG. 11 is a graph showing a mixed pattern of aripiprazole and haloalkane at an initial column temperature of 102 ℃ in the column of example 2;
FIG. 12 is a graph showing the mixing spectra of aripiprazole and haloalkane at a split ratio of 9:1 in example 2;
FIG. 13 is a graph showing the mixing pattern of aripiprazole and haloalkane at a split ratio of 11:1 in example 2;
FIG. 14 is the linear results of 1, 4-dichlorobutane in example 5;
FIG. 15 is the linear results for 1-bromo-4-chlorobutane in example 5;
FIG. 16 shows the linear results of 1, 4-dibromobutane in example 5.
Detailed Description
The invention provides a method for detecting genotoxic impurity halogenated alkane in aripiprazole, which comprises the following steps:
(1) dissolving aripiprazole in a solvent to obtain a test solution;
(2) dissolving a reference substance of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in a solvent to obtain a reference substance solution;
(3) respectively carrying out gas chromatography-mass spectrometry detection on the test solution and the reference solution to obtain a spectrogram of a solution to be detected and a spectrogram of the reference solution, and calculating by using an external standard method to obtain the contents of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the aripiprazole;
the step (1) and the step (2) have no requirement of time sequence.
The source of the aripiprazole has no special requirement, and the aripiprazole needing to be subjected to genotoxic impurity halogenated alkane detection can be detected by using the method disclosed by the invention. In the invention, the aripiprazole genotoxic impurity halogenated alkane is specifically 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane, and the chemical structural formula is shown in table 1:
TABLE 1 chemical structural formula of aripiprazole genotoxic impurity haloalkane
The invention dissolves the aripiprazole in the solvent to obtain the test solution. In the present invention, the solvent preferably includes one or more of dichloromethane, chloroform, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, and N-methylpyrrolidone, and more preferably dichloromethane; the concentration of the aripiprazole in the test solution is preferably 9-11 mg/mL, and more preferably 10 mg/mL.
In the embodiment of the present invention, it is preferable to weigh an appropriate amount of aripiprazole raw material, precisely weigh it, dissolve it with a solvent, and then quantitatively dilute it to achieve the desired concentration.
In the invention, a reference substance of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane is dissolved in a solvent to obtain a reference substance solution. In the present invention, the solvent preferably includes one or more of dichloromethane, chloroform, dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone, and more preferably dichloromethane, and the solvents of the test solution and the control solution are consistent; the concentration of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the control solution is independently preferably 0.4-0.6 mu g/mL, and more preferably 0.5 mu g/mL; the invention has no special requirements on the reference substances of the 1, 4-dichlorobutane, the 1-bromo-4-chlorobutane and the 1, 4-dibromobutane, and only needs to use the reference substances sold in the market.
In the embodiment of the present invention, it is preferable to first weigh an appropriate amount of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane, and 1, 4-dibromobutane, then dissolve with a solvent and quantitatively dilute to achieve the desired concentration.
After a test solution and a reference solution are obtained, the gas chromatography-mass spectrometry detection is respectively carried out on the test solution and the reference solution to obtain a spectrogram of a solution to be detected and a spectrogram of the reference solution. In the invention, the sample amount of the test solution and the reference solution in the gas chromatography-mass spectrometry detection is preferably 1 μ L.
In the present invention, the gas chromatography-mass spectrometry detection preferably has the following gas chromatography conditions:
a chromatographic column: a capillary column taking 6% of cyanopropylphenyl-94% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 35% of diphenyl-65% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 5% of diphenyl-95% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 50% of diphenyl-50% of dimethylpolysiloxane as a stationary liquid;
carrier gas: helium gas;
flow rate: 0.9mL/min to 1.1 mL/min;
temperature programming: the initial column temperature of the chromatographic column is 98-102 ℃, the initial column temperature is kept for 5min, the temperature is raised to 150 ℃ at the speed of 5 ℃/min, and the initial column temperature is kept for 2 min;
sample inlet temperature: 180 ℃;
the split ratio is as follows: 11: 1-9: 1.
Among them, the flow rate is more preferably 1mL/min, the split ratio is more preferably 10:1, and the initial column temperature of the column is more preferably 100 ℃.
In the present invention, the mass spectrometric conditions for the gas chromatography-mass spectrometry detection are preferably: the temperature of a transmission line is 190-210 ℃, the temperature of an ion source is 220-240 ℃, the temperature of a four-level bar is 140-160 ℃, the detection mode is Selected Ion Monitoring (SIM), and the extracted ions are m/z55.00, m/z91.00 and m/z 135.00; residence time is 100ms, solvent delay time is 4min, low resolution mode; wherein the transfer line temperature is more preferably 200 ℃, the ion source temperature is more preferably 230 ℃, and the quadrupole temperature is more preferably 150 ℃.
The method controls the gas chromatography-mass spectrometry detection conditions within the range, each halogenated alkane has good response, the blank reagent and the sample do not interfere, the separation degree, the theoretical plate number and the symmetry factor of each peak in the spectrogram are good, and the method can accurately detect various genotoxic impurity halogenated alkanes in the aripiprazole.
After the spectrogram is obtained, the content of the 1, 4-dichlorobutane, the 1-bromo-4-chlorobutane and the 1, 4-dibromobutane in the aripiprazole is obtained by calculating by using an external standard method according to the peak area of the spectrogram. The specific calculation method of the external standard method has no special requirement, and the calculation can be carried out by using the external standard method well known by the technical personnel in the field.
The reagents used in the present invention are, unless otherwise specified, reagents of chromatographic grade.
The embodiments of the present invention will be described in detail with reference to the following examples, but they should not be construed as limiting the scope of the present invention.
Instruments and reagents used in the examples of the invention:
the instrument comprises the following steps: XS 205; agilent 7890B-MS; column DB-624(30m × 0.25mm × 1.4 μm).
Solvent: dichloromethane (HPLC, TEDIA)
Reagent testing: aripiprazole raw material (manufacturer: Jiangsu Haikei biological pharmaceutical Co., Ltd., Yangzjiang pharmaceutical group, batch No. JP-18062901).
Comparison products: 1-bromo-4-chlorobutane (99.66% content, from Doutaxin, Ltd., batch No. 18-01-01); 1, 4-dibromobutane (content: 99.56%, manufacturer: damas-beta, lot: P1319228)1, 4-dichlorobutane (content: 99.77%, manufacturer: damas-beta, lot: P1027353)
Example 1
Specificity and system applicability experiments:
the conditions of gas chromatography-mass spectrometry detection in this example were:
gas chromatography conditions: directly feeding samples: 1 mu L of the solution; a chromatographic column: a capillary column with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the stationary liquid was used as the chromatographic column (Agilent DB-624, 30 m.times.0.25 mm.times.1.4 μm); the carrier gas is helium; flow rate: 1.0 mL/min; temperature programming: the initial temperature is 100 ℃, the temperature is kept for 5 minutes, the temperature is raised to 150 ℃ at the rate of 5 ℃ per minute, and the temperature is maintained for 2 minutes; the temperature of a sample inlet is 180 ℃; the split ratio is 10: 1;
mass spectrum conditions: the temperature of a transmission line is 200 ℃, the temperature of an ion source is 230 ℃, the temperature of a four-level bar is 150 ℃, and the ion extraction is in an m/z55.00 mode in an ion monitoring mode (SIM); m/z 91.00; m/z135.00, residence time 100ms, solvent delay time 4 minutes, low resolution mode.
The specificity is as follows:
(1) firstly, detecting a blank solvent dichloromethane, wherein the obtained spectrogram is shown in figure 1; as can be seen from fig. 1, the solvent does not interfere with the detection of various impurities;
(2) respectively dissolving 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in dichloromethane to obtain a 1, 4-dichlorobutane solution, a 1-bromo-4-chlorobutane solution and a 1, 4-dibromobutane positioning solution which are all at the concentration of 5 mu g/mL;
dissolving 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in dichloromethane, and diluting to obtain solutions containing 0.5 μ g of each of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane per 1mL as control solutions;
dissolving aripiprazole in dichloromethane to obtain an aripiprazole solution (i.e. a test solution) with a concentration of 10 mg/mL;
mixing 18mL of aripiprazole solution and 2mL of reference solution to obtain an aripiprazole-halogenated alkane mixed solution.
Respectively carrying out gas chromatography-mass spectrometry detection on a 1, 4-dichlorobutane solution, a 1-bromo-4-chlorobutane solution, a 1, 4-dibromobutane solution, a reference substance solution, an aripiprazole solution and an aripiprazole-halogenated alkane mixed solution, wherein the obtained results are shown in figures 2-7; according to the figures 2-7, under the detection condition of the invention, the separation degrees of the 1, 4-dichlorobutane, the 1-bromo-4-chlorobutane and the 1, 4-dibromobutane are good, and the blank solvent and the aripiprazole sample do not interfere with the detection of each impurity, which shows that the detection method of the invention has good specificity.
The system applicability is as follows: as can be seen from FIG. 7, the separation degree among the impurities is more than or equal to 2.0, and the number of theoretical plates of each impurity meets the requirement, which shows that the detection method of the invention has good system applicability.
Example 2
And (3) durability test:
the preparation method of the aripiprazole-haloalkane mixed solution is the same as that of example 1.
Respectively setting the flow rate in the gas chromatography condition to be 0.9mL/min and 1.1mL/min, and performing gas chromatography-mass spectrometry detection on the aripiprazole-halogenated alkane mixed solution under the other conditions consistent with those of example 1 to obtain spectrograms shown in figures 8-9;
the initial temperatures of the chromatographic columns in the gas chromatography conditions were set to 98 ℃ and 102 ℃ respectively, and other conditions were the same as in example 1, and the gas chromatography-mass spectrometry detection was performed on the aripiprazole-haloalkane mixed solution, and the obtained spectra were shown in fig. 10 to 11.
Respectively setting the split ratio of 9:1 and 11:1 in the gas chromatography conditions, and performing gas chromatography-mass spectrometry detection on the aripiprazole-haloalkane mixed solution under the other conditions consistent with those of example 1 to obtain spectrograms shown in figures 12-13;
as can be seen from FIGS. 8 to 13, when the flow rate of the gas chromatography is 0.9 to 1.1mL/min, the split ratio is 9:1 to 11:1, and the initial column temperature of the chromatographic column is 98 to 102 ℃, the test sample does not interfere with the detection of the halogenated alkanes, and the separation degree is good, which indicates that the detection method of the invention has good durability.
Example 3
And (3) detecting the stability of the solution:
the preparation method of the test solution and the control solution is the same as that of example 1, the gas chromatography-mass spectrometry detection is carried out on the test solution and the control solution at 0h, 2h, 4h, 6h, 8h, 12h, 16h and 24h respectively, the detection conditions are the same as that of example 1, and the obtained results are shown in table 2:
TABLE 2 stability test results for aripiprazole solution and control solution
As can be seen from Table 2, the deviations of the peak areas in the reference solution and the test solution within 24h from 0h are less than 20%, which indicates that the two solutions can be kept stable after being placed for 24 h.
Example 4
Detection limit and quantification limit:
precisely weighing 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane, placing the weighed materials in a bottle, dissolving the materials with dichloromethane to prepare stock solution, gradually diluting the stock solution, respectively injecting samples to carry out gas chromatography-mass spectrometry detection, wherein the detection conditions are consistent with those of example 1; the signal-to-noise ratio (peak height/baseline noise) 3 + -1 is used as the detection limit, and the signal-to-noise ratio 10 + -2 is used as the quantification limit.
The results show that the limit of quantitation and the limit of detection of each impurity are both much less than 50ppm, where: the quantitative limits of 1, 4-dichloromethane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane were 0.0194ng/mL, 0.0200ng/mL and 0.0304ng/mL, respectively.
Example 5
Linear relationship and linear range:
linear solutions were prepared in which the concentrations of the respective impurities were within 200% of the quantitative limit to the limit concentration (50ppm), gas chromatography-mass spectrometry was performed (the concentration was taken at 25% of the quantitative limit and the limit concentration, 50% of the limit concentration, 100% of the limit concentration, 150% of the limit concentration, and 200% of the limit concentration), and the detection conditions were the same as those in example 1, and linear regression was performed using the concentration as abscissa and the peak area as ordinate, and the results were shown in fig. 14 to 16, in which fig. 14 is a linear result of 1, 4-dichlorobutane; FIG. 15 shows the linear results for 1-bromo-4-chlorobutane; FIG. 16 shows the linear results of 1, 4-dibromobutane; as can be seen from FIGS. 14 to 16, the linear relationship between the peak area and the concentration was good in the range of 200% from the quantitation limit to the limit concentration (50 ppm).
Example 6
And (3) testing accuracy: the accuracy of the method is tested by adding halogenated alkane with 50 percent limit concentration, 100 percent limit concentration and 150 percent limit concentration into a test solution, and the steps are as follows:
(1) accurately preparing 1, 4-dichlorobutane solutions with the concentrations of 5.04 mug/mL and 4.97 mug/mL as stock solution 1 and stock solution 2;
taking out stock solution 1 and stock solution 21mL respectively, and fixing the volume to 10mL by using dichloromethane to obtain 1, 4-dichlorobutane solutions with the concentrations of 0.504 mu g/mL and 0.497 mu g/mL, respectively recording as samples DZ-1 and DZ-2, carrying out gas chromatography-mass spectrometry detection on the samples DZ-1 and DZ-2, calculating a correction factor, carrying out parallel test for 3 times, wherein the test conditions are consistent with those of the example 1;
weighing 200mg of aripiprazole sample to be tested, placing the aripiprazole sample into a 20mL measuring flask, adding 1mL (50% limit concentration)/2 mL (100% limit concentration)/3 mL (150% limit concentration) stock solution 1(5.04 mu g/mL) respectively, then fixing the volume by using dichloromethane, carrying out gas chromatography-mass spectrometry detection according to the conditions, and calculating the recovery rate, wherein the obtained results are shown in tables 3-4;
TABLE 3 correction factor test results
TABLE 4 recovery test results
GSP in Table 4 represents the test solution without added standard;
(2) preparing a 1-bromo-4-chlorobutane solution according to the method in the step (1), and performing a correction factor test and a recovery rate test, wherein the obtained results are shown in tables 5-6;
TABLE 5 correction factor test results
TABLE 6 recovery test results
GSP in Table 6 represents the test solution without added standard;
(3) preparing a 1, 4-dibromobutane solution according to the method in the step (1), and performing a correction factor test and a recovery rate test, wherein the obtained results are shown in tables 7-8;
TABLE 7 correction factor test results
TABLE 8 recovery test results
GSP in Table 8 represents the test solution without added standard;
according to the test results in tables 3-8, the recovery rate of the detection method disclosed by the invention is 100.50-104.41%, and the relative standard deviation is 1-1.2%. The method has good accuracy and reliable measuring result.
The embodiment shows that the detection method provided by the invention has good specificity and durability, and the detection of halogenated alkane as the toxic impurity of the aripiprazole gene cannot be influenced by changing chromatographic conditions such as flow rate, initial column temperature, split flow ratio and the like within a small range; the method provided by the invention can accurately detect various genotoxic impurities in the aripiprazole.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A method for detecting genotoxic impurity halogenated alkane in aripiprazole is characterized by comprising the following steps:
(1) dissolving aripiprazole in a solvent to obtain a test solution;
(2) dissolving a reference substance of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in a solvent to obtain a reference substance solution;
(3) respectively carrying out gas chromatography-mass spectrometry detection on the test solution and the reference solution to obtain a spectrogram of a solution to be detected and a spectrogram of the reference solution, and calculating by using an external standard method to obtain the contents of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the aripiprazole;
the step (1) and the step (2) have no requirement of time sequence.
2. The detection method according to claim 1, wherein the solvent in the steps (1) and (2) comprises one or more of dichloromethane, chloroform, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone.
3. The detection method according to claim 1, wherein the concentration of aripiprazole in the test solution is 9-11 mg/mL.
4. The detection method according to claim 1, wherein the concentrations of 1, 4-dichlorobutane, 1-bromo-4-chlorobutane and 1, 4-dibromobutane in the control solution are independently 0.4 to 0.6 μ g/mL.
5. The detection method according to claim 1, wherein the sample volumes of the test solution and the control solution in the gas chromatography-mass spectrometry detection are 1 μ L.
6. The detection method according to claim 1, wherein the gas chromatography-mass spectrometry detection has the following gas chromatography conditions:
a chromatographic column: a capillary column taking 6% of cyanopropylphenyl-94% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 35% of diphenyl-65% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 5% of diphenyl-95% of dimethylpolysiloxane as a stationary liquid, or a capillary column taking 50% of diphenyl-50% of dimethylpolysiloxane as a stationary liquid;
carrier gas: helium gas;
flow rate: 0.9mL/min to 1.1 mL/min;
temperature programming: the initial column temperature of the chromatographic column is 98-102 ℃, the initial column temperature is kept for 5min, the temperature is raised to 150 ℃ at the speed of 5 ℃/min, and the initial column temperature is kept for 2 min;
sample inlet temperature: 180 ℃;
the split ratio is as follows: 11: 1-9: 1.
7. The detection method according to claim 6, wherein the flow rate is 1.0mL/min, the split ratio is 10: 1; the initial column temperature of the chromatographic column was 100 ℃.
8. The detection method according to claim 1, wherein the mass spectrometric conditions of the gas chromatography-mass spectrometric detection are: the temperature of the transmission line is 190-210 ℃, the temperature of the ion source is 220-240 ℃, the temperature of the four-level bar is 140-160 ℃, the detection mode is selected ion monitoring, and the extracted ions are m/z55.00, m/z91.00 and m/z 135.00; residence time was 100ms, solvent delay time was 4min, low resolution mode.
9. The method of claim 8, wherein the transport line temperature is 200 ℃, the ion source temperature is 230 ℃, and the quadrupole temperature is 150 ℃.
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