CN114646694A - Method for separating and detecting brexpiprazole impurity by adopting gas chromatography - Google Patents
Method for separating and detecting brexpiprazole impurity by adopting gas chromatography Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 31
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960001210 brexpiprazole Drugs 0.000 title claims abstract description 24
- 238000004817 gas chromatography Methods 0.000 title claims abstract description 8
- 239000012535 impurity Substances 0.000 title claims description 29
- NIDSRGCVYOEDFW-UHFFFAOYSA-N 1-bromo-4-chlorobutane Chemical compound ClCCCCBr NIDSRGCVYOEDFW-UHFFFAOYSA-N 0.000 claims abstract description 29
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 claims abstract description 27
- KJDRSWPQXHESDQ-UHFFFAOYSA-N 1,4-dichlorobutane Chemical compound ClCCCCCl KJDRSWPQXHESDQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000004205 dimethyl polysiloxane Substances 0.000 claims abstract description 10
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims abstract description 10
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims description 39
- 239000012086 standard solution Substances 0.000 claims description 26
- 239000012085 test solution Substances 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- 238000007865 diluting Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000012159 carrier gas Substances 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000011002 quantification Methods 0.000 claims description 3
- 238000010813 internal standard method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 4
- 239000000523 sample Substances 0.000 description 37
- 239000007789 gas Substances 0.000 description 13
- 238000000926 separation method Methods 0.000 description 11
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- 239000000463 material Substances 0.000 description 9
- 230000035945 sensitivity Effects 0.000 description 8
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- 229910052757 nitrogen Inorganic materials 0.000 description 7
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- 239000013558 reference substance Substances 0.000 description 7
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- -1 4- (4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl) butoxy Chemical group 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
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- 102000017911 HTR1A Human genes 0.000 description 1
- 101150015707 HTR1A gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
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- 201000000980 schizophrenia Diseases 0.000 description 1
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 description 1
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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
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/60—Construction of the column
- G01N30/6052—Construction of the column body
- G01N30/6073—Construction of the column body in open tubular form
- G01N30/6078—Capillaries
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/64—Electrical detectors
- G01N30/68—Flame ionisation detectors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N2030/042—Standards
- G01N2030/045—Standards internal
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Abstract
The invention provides a method for separating and measuring 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in brexpiprazole, which adopts gas chromatography and takes a capillary column taking 5% of phenyl-95% of dimethylpolysiloxane as a stationary liquid as a chromatographic column. The method can be used for controlling the quality of the brexpiprazole.
Description
Technical Field
The invention belongs to the field of drug analysis methods, and particularly relates to a method for separating and determining 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in brexpiprazole by adopting a gas chromatography.
Background
Ipiprazole is an atypical antipsychotic drug co-developed by north danazol and tsukamur japan, and its mechanism of pharmacological action may be mediated by a combination of partial agonist activity at the serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at the serotonin 5-HT2A receptor. The preparation is a tablet, and the product is marketed in the United states at 10 th month 07 in 2015, 19 th month 01 in 2018 in Japan, and 27 th month 07 in 2018 in European Union, and is not marketed at home at present. It is approved for the adjuvant treatment of major depression (MDD) and for the treatment of schizophrenia.
The chemical name of the brexpiprazole is 7- (4- (4- (benzo [ b ] thiophene-4-yl) piperazine-1-yl) butoxy) quinoline-2 (1H) -ketone, and the chemical structural formula is as follows:
in the preparation process of the ipiprazole, 1-bromo-4-chlorobutane is used, so that 1-bromo-4-chlorobutane and process byproducts thereof, namely 1, 4-dichlorobutane and 1, 4-dibromobutane, which are compounds with warning structures may exist in the finished product of the ipiprazole, and the residues of the 1-bromo-4-chlorobutane, the 1, 4-dichlorobutane and the 1, 4-dibromobutane in the ipiprazole need to be controlled in order to ensure the safety of medication.
Chinese patent publication No. CN106770746B discloses a high performance liquid chromatography method for determining 1-bromo-4-chlorobutane in an ipiprazole intermediate by using a standard curve method, but the method has low sensitivity, and the limit of quantification of 1-bromo-4-chlorobutane is 25.8ng according to the signal-to-noise ratio of 10: 1; with a signal-to-noise ratio equal to 3: 1, the detection limit of 1-bromo-4-chlorobutane is 7.74ng, and the requirement of genotoxic impurity limit cannot be met.
At present, no detection method for 1, 4-dichlorobutane impurities and 1, 4-dibromobutane impurities in brexpiprazole is reported.
Therefore, it is necessary to establish an analytical detection method which is simple and effective to operate and has sensitivity meeting the requirement of genotoxic impurity limit for the analytical detection of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane impurities in the brexpiprazole.
Disclosure of Invention
The invention provides a gas chromatography method for measuring 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in ipiprazole by using 1, 4-dioxane as an internal standard. The method can simultaneously realize effective separation of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane, 1, 4-dibromobutane and an internal standard substance in the brexpiprazole, and accurately and quickly detect the 1-bromo-4-chlorobutane, the 1, 4-dichlorobutane and the 1, 4-dibromobutane in the brexpiprazole bulk drug, thereby controlling the quality of the brexpiprazole and ensuring the safety of the brexpiprazole drug.
The technical scheme adopted by the invention is as follows:
a method for separating and measuring 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in ipiprazole by gas chromatography comprises the steps of taking a capillary column with 5% of phenyl-95% of dimethylpolysiloxane as a stationary liquid as a chromatographic column, taking 1, 4-dioxane as an internal standard substance, taking N, N-dimethylformamide as a solvent, and detecting by using a hydrogen flame ionization detector (FID detector).
The method of the invention further comprises the following steps:
a. preparation of internal standard solution: taking a proper amount of 1, 4-dioxane, placing the mixture into a brown measuring flask, adding N, N-dimethylformamide for dissolving, and gradually diluting to prepare a solution containing 5.3 mu g of 1, 4-dioxane in each 1ml as an internal standard solution;
b. preparation of a test solution: placing the brexpiprazole in a brown measuring flask, dissolving and diluting by using an internal standard solution to prepare a solution containing about 10mg of brexpiprazole in each 1ml as a test solution;
c. preparing a reference substance solution: precisely weighing 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane, placing into a brown measuring flask, adding an internal standard solution, dissolving and diluting to obtain solutions each containing 3.75 μ g of the internal standard solution per 1ml, and using the solutions as control solutions;
d. the chromatographic conditions were as follows: a capillary column taking 5% of phenyl-95% of dimethyl polysiloxane as a stationary liquid is taken as a chromatographic column; taking nitrogen as carrier gas; the flow rate of the carrier gas is 1.1-1.3 ml/min; the initial temperature is 75-85 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes; the detector is FID; the temperature of the detector is 300 ℃; the temperature of a sample inlet is 250 ℃; the split ratio is 10: 1; the sample introduction mode is direct sample introduction; the sample amount is 5 mul;
e. and respectively taking the reference substance solution and the sample solution, carrying out sample injection measurement according to the chromatographic conditions, and calculating the contents of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in the brexpiprazole by peak area according to an internal standard method.
The method has the advantages that:
In a word, the gas chromatography method can be simultaneously used for separating and measuring 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in the brexpiprazole, and has the advantages of better specificity, sensitivity, accuracy and the like, and the operation is simple.
Drawings
FIG. 1 gas chromatogram of a solvent blank;
FIG. 2 gas chromatogram for the localization of the impurity 1-bromo-4-chlorobutane;
FIG. 3 gas chromatogram for localization of impurity 1, 4-dichlorobutane;
FIG. 4 gas chromatogram for localization of impurity 1, 4-dibromobutane;
FIG. 5 gas chromatogram for impurity 1, 4-dioxane localization;
FIG. 6 gas chromatogram of a control solution;
FIG. 7 is a gas chromatogram of a test solution.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. Various modifications and improvements of the technical solution of the present invention may be made by those skilled in the art without departing from the spirit of the present invention, and the technical solution of the present invention is to be covered by the protection scope defined by the claims.
Example 1
Gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethylpolysiloxane as fixative (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.2 ml/min;
column temperature: the initial temperature is 80 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
detector temperature: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
Solution preparation:
solvent: n, N-dimethylformamide;
internal standard solution: taking a proper amount of 1, 4-dioxane, placing the mixture into a brown measuring flask, adding a solvent for dissolving, and diluting step by step to prepare a solution containing 5.3 mu g of 1, 4-dioxane in each 1ml as an internal standard solution;
impurity localization solution: precisely weighing 75mg of 1-bromo-4-chlorobutane, 75mg of 1, 4-dichlorobutane and 75mg of 1, 4-dibromobutane, respectively placing the weighed materials into 200ml brown measuring flasks, adding a solvent to dissolve and dilute the materials to a scale, shaking up, precisely weighing 1ml, respectively placing the weighed materials into 100ml measuring flasks, diluting the materials to the scale by using the solvent, and shaking up to obtain the reference substance positioning solution of each impurity;
control solution: precisely weighing 75mg of 1-bromo-4-chlorobutane, 75mg of 1, 4-dichlorobutane and 75mg of 1, 4-dibromobutane, placing the weighed materials into a 200ml brown measuring flask, adding an internal standard solution to dissolve and dilute the materials to a scale, shaking up, precisely weighing 1ml of the materials, placing the materials into a 100ml measuring flask, adding the internal standard solution to dilute the materials to the scale, and shaking up to obtain a reference solution;
preparing a test solution: 0.1g of ipiprazole is precisely weighed and placed in a 10ml brown measuring flask, and an internal standard solution is added to be dissolved and diluted to a scale mark, and the mixture is shaken up to be used as a test solution.
And (3) determination: and taking the solvent, the impurity positioning solution, the internal standard solution, the reference substance solution and the sample solution, carrying out sample injection detection according to the chromatographic conditions, and recording a chromatogram.
The maps are shown in FIGS. 1, 2, 3, 4, 5, 6 and 7, respectively. FIGS. 1, 2, 3, 4, 5 show that the target impurity can be effectively separated from the internal standard and the blank solvent peak; FIG. 6 shows that the target peak and the adjacent peaks in the control solution can be effectively separated, the separation degree is greater than 1.5, and the data are shown in Table 1; FIG. 7 shows that none of the target impurities was detected in the test sample solution.
Table 1 impurity localization retention time and resolution results
Example 2 methodological validation
In the method verification, the chromatographic conditions are as follows:
gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethylpolysiloxane as fixative (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.2 ml/min;
column temperature: the initial temperature is 80 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
detector temperature: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
1. Linearity and range
Taking appropriate amount of reference substances of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane, diluting with internal standard solution to obtain series of linear solutions, injecting sample according to the above chromatographic conditions, and recording chromatogram.
The results show that: when the concentration of the 1, 4-dichlorobutane is within the range of 0.38 mu g/ml to 5.64 mu g/ml, the good linearity is realized between the concentration of the 1, 4-dichlorobutane and the peak area of a to-be-detected object/the peak area of an internal standard object, the regression equation is Y = -0.0121+0.2768 xX (wherein X is the concentration, mu g/ml; Y is the ratio of the peak area of the to-be-detected object to the peak area of the internal standard object), and the correlation coefficient is R = 0.9998; when the concentration of the 1-bromo-4-chlorobutane is within the range of 0.38 mu g/ml to 5.66 mu g/ml, the linear relationship between the peak area of the 1-bromo-4-chlorobutane and the peak area of the to-be-detected object/the peak area of the internal standard object is good, the regression equation is Y = -0.0029+0.1953 xX (wherein X is the concentration, mu g/ml; Y is the ratio of the peak area of the to-be-detected object to the peak area of the internal standard object), and the correlation coefficient is R = 0.9994; when the concentration of the 1, 4-dibromobutane is within the range of 0.38 mu g/ml to 5.69 mu g/ml, the good linearity is achieved with the peak area of the object to be detected/the peak area of the internal standard substance, the regression equation is Y = -0.0089+0.1495 xX (wherein X is the concentration, mu g/ml; Y is the ratio of the peak area of the object to be detected to the peak area of the internal standard substance), and the correlation coefficient is R =0.9989, and the requirements are met.
2. System applicability and sample introduction precision
A control solution was prepared by the method of example 1, and 6 needles were continuously injected under the above-mentioned chromatographic conditions, and a chromatogram was recorded. The results are shown in tables 2 and 3:
TABLE 2 number of theoretical plates
TABLE 3 sample introduction precision
From the results, it can be seen that: the RSD of the ratio of each residual solvent peak area to the internal standard substance peak area is less than 10.0 percent, the number of theoretical plates of each solvent peak is more than 5000, and the requirement is met.
3. Confirmation of quantitative limits
Taking appropriate amount of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane respectively, precisely weighing, and diluting with internal standard solution to obtain quantitative limit confirmation solutions with concentrations of 0.77 μ g/ml, 0.76 μ g/ml and 0.74 μ g/ml respectively. And (5) injecting samples according to the chromatographic conditions, and recording chromatograms.
From the results, it can be seen that: the calculation represented by 1, 4-dibromobutane with the weakest response and the lowest sensitivity is carried out, the signal-to-noise ratio is counted as 20, the quantitative limit is 0.74 mu g/ml, the sample injection amount is 5 mu l, the split ratio is 10:1, and the quantitative limit is equivalent to 0.37 ng; the method has high sensitivity and meets the detection requirement.
4. Stability of solution
Preparing a reference solution according to the method of example 1; taking 0.1g of the crude drug of the ipiprazole, precisely weighing, placing in a 10ml brown measuring flask, adding the reference solution to dissolve and dilute to a scale, and shaking up to be used as a test solution. Placing at room temperature, injecting sample according to the chromatographic conditions, recording chromatogram, and inspecting solution stability.
From the results, it can be seen that: when the brown bottle is placed at room temperature for 73 hours, the relative variation of the ratio of the main peak area of each impurity to the main peak area of the internal standard substance in the reference solution and the test solution is less than 20%, which indicates that the reference solution and the test solution are stable in the time period.
5. Repeatability of
Preparing reference solution and 6 parts of test solution according to the method under the item of '4 and solution stability', injecting sample according to the chromatographic conditions, and recording chromatogram. The results are shown in Table 4:
TABLE 4 results of the repeatability tests
From the results, it can be seen that: RSD of each impurity content is 1.32%, 1.37% and 1.93%, and repeatability is good.
6. Intermediate precision
Different analysts take the same batch of brexpiprazole at different time, prepare a reference solution and a test solution under the item of '5 and repeatability', test 6 parts in parallel, and calculate the RSD of the residual quantity of each impurity. The results are shown in Table 5:
TABLE 5 results of intermediate precision test
From the results, it can be seen that: and through comprehensive calculation with a repeatability result, the content of each impurity RSD is 1.69%, 2.89% and 3.51%, and the intermediate precision is good.
7. Accuracy of
Internal standard solution: the procedure was as in example 1.
Preparing a stock solution: respectively weighing 75mg of 1-bromo-4-chlorobutane, 75mg of 1, 4-dichlorobutane and 75mg of 1, 4-dibromobutane, precisely weighing, placing in a 200ml brown measuring flask, adding an internal standard solution to dissolve and dilute to a scale, shaking up, precisely weighing 5ml, placing in a 50ml measuring flask, diluting to a scale with the internal standard solution, and shaking up.
Preparing a reference substance solution: precisely measuring 1ml of the stock solution, placing the stock solution into a 10ml brown measuring flask, diluting the stock solution to a scale with an internal standard solution, and shaking up to obtain the finished product.
Preparing an accuracy test solution: accurately weighing 0.1g of ipiprazole, paralleling 12 parts of ipiprazole, putting the ipiprazole into a 10ml brown measuring flask, accurately adding 3 parts of the eiprazole into 0.3ml of the stock solution, adding an internal standard solution, dissolving and diluting the stock solution to a scale, and shaking up to be used as a sample solution with the accuracy of 30 percent of the limit; wherein 3 parts of the test solution are precisely added into 1ml of the stock solution, then an internal standard solution is added for dissolution and dilution to scale, and the solution is shaken up and is used as a test solution with limited concentration accuracy; wherein 3 parts of the test solution are precisely added into 1.5ml of the stock solution, then an internal standard solution is added for dissolution and dilution to scale, and the solution is shaken up and is used as a test sample solution with the accuracy equivalent to the limit concentration of 150%; wherein 3 parts of the solution is precisely added with the internal standard solution to be dissolved and diluted to a scale, and is shaken up to be used as a background test sample solution.
And taking the reference substance solution and the accuracy test sample solution, injecting sample according to the chromatographic conditions, and recording a chromatogram. The results are shown in Table 6:
TABLE 6 accuracy test results
From the results, it can be seen that: the accuracy of each impurity determination is high, and the RSD of the same concentration level is small.
In conclusion, the method can effectively detect the 1-bromo-4-chlorobutane, the 1, 4-dichlorobutane and the 1, 4-dibromobutane in the brexpiprazole bulk drug under the chromatographic condition, and has the advantages of high sensitivity, strong specificity, high accuracy and simple and convenient operation.
Example 3
Gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethylpolysiloxane as fixative (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.1 ml/min;
column temperature: the initial temperature is 80 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
detector temperature: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
The control solution was tested according to example 1 and showed a separation of greater than 1.5 between the target peak and the adjacent peak, and the separation data is shown in table 7:
table 7 impurity separation results
Example 4
Gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethyl polysiloxane as fixing liquid (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.3 ml/min;
column temperature: the initial temperature is 80 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
detector temperature: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
The control solution was tested as in example 1 and showed a degree of separation of the target peak from the adjacent peaks of greater than 1.5, as shown in Table 8:
table 8 results of degree of impurity separation
Example 5
Gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethylpolysiloxane as fixative (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.2 ml/min;
column temperature: the initial temperature is 75 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
temperature of the detector: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
The control solution was tested as in example 1 and showed a degree of separation of the target peak from the adjacent peaks of greater than 1.5, as shown in Table 9:
TABLE 9 impurity separation results
Example 6
Gas chromatograph: agilent 7890B;
a chromatographic column: 5% phenyl-95% dimethylpolysiloxane as fixative (DB-5, 30m × 0.53mm, 5.00 μm);
carrier gas flow rate (nitrogen): 1.2 ml/min;
column temperature: the initial temperature is 85 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 minutes;
a detector: FID;
detector temperature: 300 ℃;
sample inlet temperature: 250 ℃;
the split ratio is as follows: 10: 1;
and (3) sample introduction mode: directly feeding a sample;
sample introduction amount: 5 μ l.
The control solution was tested as in example 1 and showed a degree of separation of the target peak from the adjacent peaks of greater than 1.5, as shown in Table 10:
TABLE 10 results of degree of impurity separation
Claims (7)
1. The method for determining the impurities of the brexpiprazole by adopting the gas chromatography is characterized in that the impurities are 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane, the method adopts an internal standard method for quantification, a capillary column of 5% phenyl-95% dimethylpolysiloxane is taken as a chromatographic column, 1, 4-dioxane is taken as an internal standard substance, N-dimethylformamide is taken as a solvent, and a FID detector is adopted for detection.
2. The method of claim 1, wherein the detection conditions are:
carrier gas: nitrogen gas;
flow rate of carrier gas: 1.1-1.3 ml/min;
column temperature: the initial temperature is 75-85 ℃, the temperature is increased to 220 ℃ at the rate of 15 ℃ per minute, and the temperature is maintained for 10 min;
detector temperature: 300 ℃;
sample inlet temperature: at 250 deg.c.
3. The method of claim 1, having a split ratio of 10:1, the sample injection mode is direct sample injection, and the sample injection amount is 5 mul.
4. The method of claim 2, wherein the carrier gas flow rate is 1.2 ml/min.
5. The process of claim 2, wherein the column temperature has an onset temperature of 80 ℃.
6. The method of claim 1, wherein the internal standard solution, the test solution and the control solution are prepared using N, N-dimethylformamide as a solvent.
7. The method of claim 6, wherein the internal standard solution, the test solution and the control solution are prepared by the following method:
1) internal standard solution: taking a proper amount of 1, 4-dioxane, placing the mixture into a brown measuring flask, adding N, N-dimethylformamide to dissolve and dilute the mixture to prepare a solution containing 5.3 mu g of 1, 4-dioxane per 1ml, thus obtaining the product;
2) test solution: placing the brexpiprazole in a brown measuring flask, dissolving and diluting the brexpiprazole with an internal standard solution to prepare a solution containing 10mg of brexpiprazole in each 1ml of the brexpiprazole, thus obtaining the brexpiprazole;
3) control solution: taking a proper amount of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane, placing the mixture into a brown measuring flask, adding an internal standard solution, dissolving and diluting to obtain solutions containing 3.75 mu g of 1-bromo-4-chlorobutane, 1, 4-dichlorobutane and 1, 4-dibromobutane in each 1ml of the mixture, and thus obtaining the product.
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