Method for detecting related substances in n-butyl bromide

Abstract

The invention provides a method for detecting related substances in n-butyl bromide, which adopts a gas chromatographic method, and the chromatographic conditions are as follows: the chromatographic column is TM-624 (60m * 0.32 mm, 2 [mu] m), and the filler is 6%-cyanopropyl phenyl-94% dimethyl polysiloxane; the detector is a hydrogen flame ionization detector; the temperature programming condition is that the initial temperature is kept at 90 DEG C for 20 minutes, and the temperature is raised to 130 DEG C at the speed of 10 DEG C per minute and kept for 5 minutes; the temperature of a sample inlet is 210 DEG C; the temperature of a detector is 240 DEG C; the carrier gas is nitrogen; the split ratio is 1: 30; the sample injection volume is 1 microliter. The methodology verification shows that the detection method is good in specificity, durability and system applicability and high in repeatability and precision, and separation and detection of related substances such as bromo-iso-butane, bromo-sec-butane, n-butyl ether, bromoethane, bromopentane, n-butyl alcohol and bromo-tert-butane in bromo-n-butane can be achieved.

Description

Technical Field

[0001] The invention belongs to the field of chemical analysis, and in particular relates to a method for detecting related substances in n-butyl bromide. Background Art

[0002] n-Butyl bromide is an important organic synthesis intermediate. It is used as a butylating agent (introducing n-butyl) in the synthesis of butylphthalide. Its purity has an important influence on the quality of butylphthalide API. Therefore, it is necessary to effectively control the related substances of n-butane bromide.

[0003] There are few reports on the related substances in n-butyl bromide and the separation and detection methods. Patent application CN119224199A provides a method for detecting related substances in n-butyl bromide. The method adopts gas chromatography detection method and only realizes the separation and detection of n-butyl bromide and its main impurity n-butyl alcohol. According to the main synthesis process of n-butyl bromide, there may be a variety of impurities in n-butyl bromide. Therefore, it is urgent to develop a related substance detection method that can detect more impurities and has good specificity, sensitivity and accuracy, so as to more strictly control the quality of n-butyl bromide, thereby realizing accurate and effective control of the quality of butylphthalide and ensuring the safety of medication. Summary of the invention

[0004] The purpose of the present invention is to provide a method for detecting related substances in n-butyl bromide, so as to achieve quality monitoring of n-butyl bromide and thus ensure the quality and safety of butylphthalide drugs.

[0005] The present invention is achieved by providing a method for detecting related substances in n-butyl bromide, characterized in that it comprises the following steps:

[0006] Step (1) Sample configuration:

[0007] Preparation of test solution: Take 1.0 g of n-butyl bromide, place in a 10 mL volumetric flask, add methanol to dilute to the mark, and shake well;

[0008] Preparation of mixed solution: Take appropriate amount of n-butyl bromide, sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide, and dilute with methanol to make a solution containing 1 mg of n-butyl bromide, 1 μg of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide per 1 mL;

[0009] Step (2) Chromatographic conditions and injection procedure:

[0010] Measure 1 μL of the test solution and the mixed solution and inject them into the gas chromatograph, perform detection according to the programmed temperature, and record the chromatogram;

[0011] A chromatographic column with 6%-cyanopropylphenyl-94% dimethylpolysiloxane as filler (or a chromatographic column with equivalent performance) is used; the detector is a hydrogen flame ionization detector; the programmed temperature is: the initial column temperature is 85-100°C, maintained for 20 minutes; the temperature is increased to 130°C at a rate of 10°C per minute, and maintained for 5 minutes; the injection port temperature is 210°C; the detector temperature is 240°C; the carrier gas is nitrogen; the split ratio is 1:30; the injection volume is 1 μL.

[0012] Furthermore, the related substances are one or more of isobutyl bromide, sec-butyl bromide, tert-butyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, and n-butanol; the related substances are all process impurities in the synthesis process of n-butyl bromide, or degradation impurities in the storage process.

[0013] Furthermore, the test solution in step (1) is prepared with methanol.

[0014] Furthermore, the specification of the chromatographic column in step (2) is 60m×0.32mm, 2μm.

[0015] Furthermore, the initial column temperature in step (2) is 90°C.

[0016] Furthermore, the method for calculating the content of the relevant substances in step (2) is the principal component self-control method with the addition of a correction factor.

[0017] The present invention has the following beneficial effects:

[0018] The detection method of the present invention can effectively separate and detect 7 related substances in n-butyl bromide, and the method has good specificity, durability, system applicability, repeatability and precision. N-butyl bromide is one of the raw materials for the preparation of butylphthalide drugs. Quality monitoring of its production process is helpful to improve the quality control of butylphthalide drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the chromatogram of the test product (batch number 2209081040157) in Example 1.

[0020] Figure 2 It is the chromatogram of the test product (batch number J2116887) in Example 1.

[0021] Figure 3 This is the chromatogram of the test sample at a column temperature of 85°C in Example 2.

[0022] Figure 4 It is the chromatogram of the test sample at a column temperature of 90° C. in Example 2.

[0023] Figure 5 It is the chromatogram of the test sample at a column temperature of 95° C. in Example 2.

[0024] Figure 6 It is the chromatogram of the blank solvent methanol in Example 3.

[0025] Figure 7 It is the chromatogram of the test product in Example 3.

[0026] Figure 8 It is the chromatogram of the reference substance in Example 3.

[0027] Fig. 9 It is the linear relationship diagram of peak area-concentration of sec-butyl bromide in Example 3.

[0028] Fig.10 It is the linear relationship diagram of peak area-concentration of isobutane bromide in Example 3.

[0029] Fig.11 This is a linear relationship diagram of peak area-concentration of n-butane bromide in Example 3.

[0030] Fig.12 This is the linear relationship diagram of the peak area-concentration of n-butyl ether in Example 3.

[0031] Fig.13 It is the linear relationship diagram of the peak area-concentration of ethyl bromide in Example 3.

[0032] Fig.14 It is the linear relationship diagram of bromopentane peak area-concentration in Example 3.

[0033] Fig.15 This is the linear relationship diagram of the peak area-concentration of n-butanol in Example 3

[0034] Fig.16 It is the linear relationship diagram of peak area-concentration of tert-butyl bromide in Example 3. DETAILED DESCRIPTION

[0035] The present invention is further described below in conjunction with comparative examples and embodiments. The following embodiments are only for illustration and are not intended to limit the scope of protection of the present invention in any form.

[0036] Sample n-Butyl Bromide Source:

[0037] batch number J2116887 2209081040157 C15545276 Specification Starting Materials Starting Materials Starting Materials Manufacturer aladdin Yancheng Longsheng Chemical Co., Ltd. MACKLIN

[0038] Source of reference material:

[0039] name batch number purity source n-Butane bromide J2116887 100％ aladdin Sec-Butane Bromide D1621006 100％ aladdin Isobutane bromide I1419007 98.12％ aladdin n-butyl ether C10037835 99.421％ Macklin Ethyl bromide J2211366 99.535％ aladdin Pentyl bromide C14499210 99.258％ Macklin n-Butanol 20230901 99％ Tianjin Damao Chemical Reagent Factory Tert-Butyl Bromide C14946838 98.017％ Macklin

[0040] Example 1 Test sample detection

[0041] (1) Solution preparation and determination method

[0042] Test solution: Take 1.0 g of n-butyl bromide sample, place in a 10 mL volumetric flask, accurately weigh, add methanol to dilute to the mark, and shake well. In this example, two batches of samples were tested, with batch numbers 2209081040157 and J2116887 respectively.

[0043] Determination of related substances: accurately measure 1 μL of the test solution and inject it into the gas chromatograph, record the chromatogram, and calculate the content of related substances according to the main component self-reference method with correction factors. The theoretical plate number calculated based on the n-butyl bromide peak is not less than 50,000, and the resolution is not less than 1.0.

[0044] (2) Gas chromatography conditions

[0045] Gas chromatograph: Shimadzu GC2010 Plus;

[0046] Chromatographic column: TM-624 (60 m × 0.32 mm, 2 μm), with 6%-cyanopropylphenyl-94% dimethylpolysiloxane as filler;

[0047] Detector: Hydrogen flame ionization detector;

[0048] Program temperature rise: initial temperature 90℃, maintained for 20min; temperature rise to 130℃ at a rate of 10℃ / min, maintained for 5min;

[0049] Inlet temperature: 210°C;

[0050] Detector temperature: 240°C;

[0051] Carrier gas: nitrogen;

[0052] Split ratio: 1:30;

[0053] Injection volume: 1 μL.

[0054] (3) Impurity quantification method:

[0055] For related substances in the test sample, the correction factor must be multiplied when calculating the content of tert-butyl bromide and ethyl bromide. Figure 1 , Figure 2 The relative retention times and correction factors of the relevant substances are shown in Table 1, and the content determination data are shown in Table 2.

[0056] According to the requirements of ICH Q3a, the unknown impurity limit of API should be controlled within 0.1%. The content of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol and tert-butyl bromide should not exceed 0.1%, other single impurities should not exceed 0.1%, and the total impurities should not exceed 1.0%; solvent peaks and all chromatographic peaks less than 0.05% are ignored.

[0057] Table 1 Relative retention time and correction factor of related substances in n-butyl bromide

[0058] name Relative retention time Correction Factor limit n-Butane bromide 1.000 1.00 Not more than 0.1% Sec-Butane Bromide 0.846 1.01 Not more than 0.2% Isobutane bromide 0.859 1.05 Not more than 0.1% n-butyl ether 1.640 0.45 Not more than 0.1% Ethyl bromide 0.500 1.61 Not more than 0.1% n-Butanol 0.809 0.45 Not more than 0.1% Pentyl bromide 1.510 0.73 Not more than 0.1% Tert-Butyl Bromide 0.662 1.86 Not more than 0.1%

[0059] Table 2 Determination results of related substances in n-butyl bromide

[0060]

[0061] It can be seen from the data in Table 2 that in the two batches of n-butyl bromide samples, the contents of tert-butyl bromide, isobutyl bromide and n-butyl ether are all less than 0.1%, and the highest content of sec-butyl bromide is 0.163%.

[0062] Example 2 Durability Verification

[0063] The durability of the detection method was investigated at different column temperatures.

[0064] Test solution: Take 1.0 g of n-butyl bromide sample (batch number 2209081040157), place it in a 10 mL volumetric flask, weigh it accurately, add methanol to dilute to the scale, and shake well.

[0065] In this embodiment, the initial column temperature of the chromatographic column is set to 85°C, 90°C, and 95°C, respectively, and the other chromatographic conditions are the same as in Example 1. Take 1 μL of the test solution and inject it into the gas chromatograph, record the chromatogram, and calculate the content of related substances. The chromatograms of the test sample at different column temperatures are shown in Figures 3 to 5 The results of the determination of the content of the relevant substances in the test samples, i.e. the separation conditions, are shown in Table 3 and Table 4.

[0066] From Table 3 and Table 4, we can see that there are 3 known impurities and 2 unknown impurities detected in this batch of samples. Figure 1 Chromatography of test product (batch number 2209081040157) Figure 1 To. From Figures 3 to 5 It can be seen that under different initial column temperature conditions, the retention time of the main component n-butyl bromide in the chromatogram is slightly different, but the peak shape and separation are good, and the detection amount of related substances has no obvious change. It can be seen that the column temperature has little effect on the chromatographic behavior. This method uses an initial column temperature of 90℃.

[0067] Table 3 Determination results of related substance contents at different column temperatures

[0068]

[0069] Table 4 Separation of impurities at different column temperatures

[0070]

[0071] Example 3 Methodology Verification

[0072] 1. Specificity verification

[0073] Blank solvent: methanol.

[0074] Impurity localization solution: Take appropriate amounts of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide, accurately weigh them, and dilute them with methanol to prepare 7 impurity localization solutions with a solution concentration of 0.1 mg / mL.

[0075] Test solution: Take 1.0 g of n-butyl bromide (batch number C15545276), accurately weigh it, put it into a 10 mL volumetric flask, add methanol to dilute to the scale, and shake well.

[0076] Reference solution: Accurately measure 1.0 mL each of n-butyl bromide, sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentane bromide, n-butyl alcohol, and tert-butyl bromide impurity location solution, place in the same 100 mL volumetric flask, add methanol to dilute to the scale, and shake well.

[0077] The chromatogram of the blank solvent methanol is shown in Figure 6 .like Figure 6 As shown, the solvent methanol does not interfere with the determination. Figure 7 .like Figure 7 As shown, a total of 5 related substances were detected in this batch of test products (batch number C15545276): tert-butyl bromide, n-butyl alcohol, sec-butyl bromide, isobutyl bromide, n-butyl alcohol, and 1 unknown impurity was also separated. Figure 6 It can be seen that the separation effect of each substance is good. Figure 8 The separation data of related substances in the reference substance are shown in Table 5. As shown in Table 5, the separation degree of each related substance is good, all > 1.0, and the specificity of this method is good.

[0078] Table 5 Separation data of each substance in the reference substance

[0079] Retention time / min Theoretical plates Separation Ethyl bromide 8.112 126263 0.000 Tert-Butyl Bromide 10.941 104663 20.15 n-Butanol 13.125 98359 38.86 Sec-Butane Bromide 13.743 110025 3.72 Isobutane bromide 13.942 108991 1.20 n-Butane bromide 16.226 115628 12.37 Pentyl bromide 24.481 348063 46.38 n-butyl ether 26.590 353602 12.27

[0080] 2 Limit of detection and limit of quantification

[0081] Reference substance dilution: Accurately weigh sec-butyl bromide, isobutyl bromide, tert-butyl bromide, n-butyl ether, n-butyl bromide, ethyl bromide, pentane bromide, and n-butanol, and use methanol to prepare reference substance stock solutions of appropriate concentrations. Take appropriate amounts of reference substance stock solutions and dilute them to prepare reference substance dilution solutions of different concentrations. Take 1 μL for sample injection and determination. When the signal-to-noise ratio is 3:1, it is the detection limit; when the signal-to-noise ratio is 10:1, it is the quantitative limit. Sample injection and determination are carried out according to the chromatographic conditions of Example 1, and the chromatogram is recorded. The results of the detection limit and quantitative limit determination are shown in Table 6 below.

[0082] Table 6 Detection limit and quantification limit determination results

[0083]

[0084] The detection limit and quantification limit of each relevant substance met the detection requirements. The quantification limit was injected for 6 consecutive times, and the detection limit was injected for 3 consecutive times, and their RSDs were all less than 10%.

[0085] 3 Precision experiment

[0086] Precision solution: Accurately weigh 1.0g each of n-butyl bromide, sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide, place in a 10mL volumetric flask, dilute to scale with methanol, shake well, and use as stock solution I. Accurately measure 0.2mL of the above stock solution I, place in a 10mL volumetric flask, dilute to scale with methanol, shake well, and use as stock solution II. Accurately measure 0.5mL of the above stock solution II, place in the same 10mL volumetric flask, dilute to scale with methanol, shake well, and use as precision solution. Take 1μL of the precision solution, inject into gas chromatograph, inject 6 times continuously, record the peak area, calculate the precision, RSD is less than 4.0%, and the measurement results are shown in Table 7.

[0087] Table 7 Precision test data

[0088]

[0089] From the data in Table 7, it can be seen that the RSD of the peak area obtained by 6 injections of each substance is less than 4.0%, indicating that the precision of this method is good.

[0090] 4 Linear range

[0091] Linear relationship solution: Accurately weigh 1.0 g each of n-butyl bromide, sec-butyl bromide, isobutyl bromide, tert-butyl bromide, n-butyl ether, ethyl bromide, pentane bromide, and n-butyl alcohol, place in a 10 mL volumetric flask, dilute to scale with methanol, shake well, and use as stock solution I. Accurately measure 0.2 mL of each of the above stock solutions I, place in a 10 mL volumetric flask, dilute to scale with methanol, shake well, and use as stock solution II. Accurately measure the reference stock solution II, and prepare a series of solutions of different concentrations as linear series solutions.

[0092] Accurately measure 1 μL of each of the above linear relationship solutions, inject them into the gas chromatograph, record the chromatogram, and calculate the peak area. Use the peak area as the ordinate and the concentration as the abscissa to perform linear regression, fit the linear equation, and use the slope value to calculate the impurity correction factor. The linear relationship between the concentration and peak area of ​​the 8 substances is shown in Figures 9 to 16 , linear range, correction factor and other data are shown in Table 8.

[0093] Table 8 Linear equations and correction factors

[0094] Linear relationship equation Correlation coefficient Linear range (mg / mL) Correction Factor Sec-Butane Bromide y=184,024.3878x-37.7394 r＝0.9996 0.021～0.207 1.01 Isobutane bromide y=178,313.2785x+267.7056 r＝0.9995 0.022～0.216 1.05 n-Butane bromide y=186,553.6120x-237.1352 r＝0.9991 0.025～0.248 1.00 n-butyl ether y=414,670.5899x-271.3616 r＝0.9996 0.010～0.196 0.45 Ethyl bromide y=116,212.2146x-397.9132 r＝0.9992 0.020～0.305 1.61 Pentyl bromide y=256,844.4223x-1,388.9327 r＝0.9987 0.019～0.308 0.73 n-Butanol y=418,577.7863x-3,216.2560 r＝0.9992 0.011～0.331 0.45 Tert-Butyl Bromide y=100,307.7914x+2,447.1986 r＝0.9874 0.020～0.203 1.86

[0095] From the data in Table 8, it can be seen that n-butyl bromide, sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentane bromide, n-butyl alcohol, and tert-butyl bromide have a good linear relationship within their ranges.

[0096] 5 Spike recovery

[0097] The spike recovery experiment included 6 reference substances: sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentane bromide, and n-butanol.

[0098] Reference substance stock solution: accurately weigh 1.0 g each of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentane bromide, and n-butanol, place in a 10 mL volumetric flask, dilute to the mark with methanol, and shake well to prepare stock solution I; accurately weigh 0.2 mL each of stock solution I, place in a 10 mL volumetric flask, dilute to the mark with methanol, and shake well to prepare stock solution II.

[0099] Test solution: Take 1.0 g of n-butyl bromide (batch number C15545276), accurately weigh it, put it into a 10 mL volumetric flask, add methanol to dilute to the scale, and shake well.

[0100] Reference solution: Accurately measure 0.5 mL each of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentane bromide, and n-butanol stock solution II, place them in the same 10 mL volumetric flask, add methanol to dilute to the scale, and shake well.

[0101] 50% spiked test solution: Accurately weigh 1.0 g of n-butyl bromide test sample and place it in a 10 mL volumetric flask, add 0.25 mL of the above-mentioned reference stock solution II, then add methanol to dilute to the scale, shake well, and prepare three replicates in parallel.

[0102] 100% spiked test solution: Accurately weigh 1.0 g of n-butyl bromide test sample and place it in a 10 mL volumetric flask, add 0.50 mL of the above-mentioned reference stock solution II, then add methanol to dilute to the scale, shake well, and prepare three parallel copies.

[0103] 150% spiked test solution: Accurately weigh 1.0 g of n-butyl bromide test sample and place it in a 10 mL volumetric flask, add 0.75 mL of the above-mentioned reference stock solution II, then add methanol to dilute to the scale, shake well, and prepare three replicates in parallel.

[0104] Take 1 μL of the spiked test solution for injection, record the chromatogram, and calculate the recovery rate of each concentration of the spiked test solution. The recovery rate limit is 90% to 108%, and the relative standard deviation (RSD) of the 9 recovery rate data should not be greater than 6%. The recovery rate results of the 6 related substances are shown in Tables 9 to 14.

[0105] Table 9 sec-Butane bromide recovery results

[0106]

[0107] From the data in Table 9, it can be seen that the recovery rate of sec-butyl bromide ranges from 95.23% to 104.74%, with an average value of 101.03%, which meets the required limit. The RSD of the 9 recovery rate data is 3.28%, which meets the requirements.

[0108] Table 10 isobutane bromide recovery results

[0109]

[0110] From the data in Table 10, it can be seen that the recovery rate of isobutane bromide ranges from 99.30% to 106.15%, with an average value of 103.93%, which meets the required limit. The RSD of the 9 recovery rate data is 2.05%, which meets the requirements.

[0111] Table 11 n-butyl ether recovery results

[0112]

[0113] From the data in Table 11, it can be seen that the recovery rate of n-butyl ether ranges from 99.87% to 105.67%, with an average value of 104.25%, which meets the required limit. The RSD of the 9 recovery rate data is 1.74%, which meets the requirements.

[0114] Table 12 Ethyl bromide recovery results

[0115]

[0116] From the data in Table 12, it can be seen that the recovery rate of ethyl bromide ranges from 98.37% to 105.74%, with an average value of 102.99%, which meets the required limit. The RSD of the 9 recovery rate data is 2.36%, which meets the requirements.

[0117] Table 13 Bromopentane recovery results

[0118]

[0119] From the data in Table 13, it can be seen that the recovery rate of bromopentane ranges from 96.21% to 106.92%, with an average value of 101.44%, which meets the required limit. The RSD of the 9 recovery rate data is 3.90%, which meets the requirements.

[0120] Table 14 n-Butanol recovery results

[0121]

[0122]

[0123] From the data in Table 14, it can be seen that the recovery rate of n-butanol ranges from 100.51% to 106.30%, with an average value of 102.39%, which meets the required limit. The RSD of the 9 recovery rate data is 1.60%, which meets the requirements.

[0124] 6. Repeatability Experiment

[0125] Test solution: Accurately weigh about 1.0g of n-butyl bromide sample (batch number 2209081040157) and place it in a 10mL volumetric flask, add methanol to dissolve and dilute to the scale, shake well. Take 1μL of the test solution for injection, record the chromatogram, calculate the impurity content according to the main component self-control method, and repeat 6 times. Requirement: The RSD of each impurity content data obtained from 6 injections should not be greater than 4%. The repeatability test results are shown in Table 15.

[0126] Table 15 Repeatability test results

[0127]

[0128] From the data in Table 15, it can be seen that this batch of samples only contains tert-butyl bromide, sec-butyl bromide, and n-butyl ether, with average contents of 0.080%, 0.036%, and 0.006%, respectively. The RSDs of the impurity contents measured by 6 injections are 1.35%, 1.29%, and 3.07%, respectively, which meet the requirements. This method has good repeatability.

[0129] Comparative Example 1

[0130] Reference solution: Accurately measure 1.0 g each of n-butyl bromide, sec-butyl bromide, isobutyl bromide, tert-butyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, and n-butanol, place in the same 10 mL volumetric flask, dilute to the mark with methanol, and shake well; accurately measure 0.2 mL of the above mixed solution into a 10 mL volumetric flask, dilute to the mark with methanol, and shake well; accurately measure 0.5 mL of the second step dilution solution, dilute to 10 mL with methanol, and shake well.

[0131] In Comparative Example 1, a chromatographic column HP-5 was selected, and the chromatographic conditions were as follows:

[0132] Chromatographic column: HP-5 (30 m × 0.32 mm, 0.25 μm), with 5%-phenyl-95% methyl polysiloxane as filler;

[0133] Detector: Hydrogen flame ionization detector;

[0134] Program temperature rise: initial temperature 60℃, hold for 5 min; heat to 80℃ at a rate of 5℃ per minute, hold for 5 min, then heat to 120℃ at a rate of 8℃ per minute, hold for 15 min;

[0135] Inlet temperature: 240°C;

[0136] Detector temperature: 280°C

[0137] Carrier gas: nitrogen;

[0138] Split ratio: 1:30;

[0139] Injection volume: 0.4 μL.

[0140] Take 1 μL of the above reference solution and inject it into the gas chromatograph to record the chromatogram.

[0141] Comparative Example 2

[0142] The chromatographic column in Comparative Example 2 is the same as that in Comparative Example 1, but the initial temperature of the column is changed, and the chromatographic conditions are as follows:

[0143] Chromatographic column: chromatographic column filled with 5%-phenyl-95% methyl polysiloxane [HP-5 (30m×0.32mm, 0.25μm)];

[0144] Detector: flame ionization detector (FID);

[0145] Program temperature rise: initial temperature 50℃, hold for 5 min; heat to 80℃ at a rate of 5℃ per minute, hold for 5 min, then heat to 120℃ at a rate of 8℃ per minute, hold for 15 min;

[0146] Inlet temperature: 240°C;

[0147] Detector temperature: 280°C;

[0148] Carrier gas: nitrogen;

[0149] Split ratio: 1:30;

[0150] Injection volume: 0.4 μL.

[0151] Measure 1 μL of the reference solution in Comparative Example 1 and inject it into the gas chromatograph to record the chromatogram.

[0152] The results showed that in Comparative Examples 1 and 2, the chromatographic peaks of sec-butyl bromide and isobutyl bromide overlapped, and the impurity separation effect was not ideal.

[0153] Comparative Example 3

[0154] The chromatographic column was replaced with an AT.FFAP column pair. The chromatographic conditions were as follows:

[0155] Chromatographic column: chromatographic column with polyethylene glycol as stationary phase [AT.FFAP (30m×0.32mm, 0.5μm)];

[0156] Detector: flame ionization detector (FID);

[0157] Program temperature rise: initial temperature 80℃, hold for 5 min; increase the temperature to 100℃ at a rate of 10℃ per minute, hold for 30 min;

[0158] Inlet temperature: 210°C;

[0159] Detector temperature: 240°C;

[0160] Carrier gas: nitrogen;

[0161] Split ratio: 1:30;

[0162] Injection volume: 0.5 μL.

[0163] Measure 1 μL of the reference solution in Comparative Example 1 and inject it into the gas chromatograph to record the chromatogram.

[0164] Comparative Example 4

[0165] The chromatographic column was replaced with an AT.FFAP chromatographic column pair, and 1 μL of the mixed reference solution in Comparative Example 1 was injected for detection. The chromatographic conditions were as follows:

[0166] Chromatographic column: chromatographic column with polyethylene glycol as stationary phase [AT.FFAP (30m×0.32mm, 0.5μm)];

[0167] Detector: flame ionization detector (FID);

[0168] Program temperature rise: initial temperature 60℃, hold for 5 min; increase the temperature to 100℃ at a rate of 10℃ per minute, hold for 30 min;

[0169] Inlet temperature: 210°C;

[0170] Detector temperature: 240°C;

[0171] Carrier gas: nitrogen;

[0172] Split ratio: 1:30;

[0173] Injection volume: 0.5 μL.

[0174] Measure 1 μL of the reference solution in Comparative Example 1 and inject it into the gas chromatograph to record the chromatogram.

[0175] The results show that in the chromatograms of Comparative Examples 3 and 4, sec-butyl bromide and isobutyl bromide cannot be baseline separated, and the impurity separation effect is not ideal.

Claims

1. A method for detecting related substances in n-butyl bromide, characterized in that: The following steps are involved: Step (1) Sample configuration: Preparation of test solution: Take 1.0 g of n-butyl bromide, place in a 10 mL volumetric flask, add methanol to dilute to the mark, and shake well; Preparation of mixed solution: Take appropriate amount of n-butyl bromide, sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide, and dilute with methanol to make a solution containing 1 mg of n-butyl bromide, 1 μg of sec-butyl bromide, isobutyl bromide, n-butyl ether, ethyl bromide, pentyl bromide, n-butyl alcohol, and tert-butyl bromide per 1 mL; Step (2) Chromatographic conditions and injection procedure: Measure 1 μL of the test solution and the mixed solution and inject them into the gas chromatograph, perform detection according to the programmed temperature, and record the chromatogram; A chromatographic column with 6%-cyanopropylphenyl-94% dimethylpolysiloxane as filler (or a chromatographic column with equivalent performance) is used; the detector is a hydrogen flame ionization detector; the programmed temperature is: the initial column temperature is 85-100°C, maintained for 20 minutes; the temperature is increased to 130°C at a rate of 10°C per minute, and maintained for 5 minutes; the injection port temperature is 210°C; the detector temperature is 240°C; the carrier gas is nitrogen; the split ratio is 1:30; the injection volume is 1 μL.

2. The method for detecting related substances in n-butyl bromide according to claim 1, characterized in that: The related substances are one or more of isobutyl bromide, sec-butyl bromide, tert-butyl bromide, n-butyl ether, ethyl bromide, pentane bromide and n-butanol.

3. The method for detecting related substances in n-butyl bromide according to claim 1, characterized in that: The test solution described in step (1) is prepared with methanol.

4. The method for detecting related substances in n-butyl bromide according to claim 1, characterized in that: The specification of the chromatographic column in step (2) is 60m×0.32mm, 2μm.

5. The method for detecting related substances in n-butyl bromide according to claim 1, characterized in that: The initial column temperature in step (2) is 90°C.

6. The method for detecting related substances in n-butyl bromide according to claim 1, characterized in that: The method for calculating the content of the relevant substances in step (2) is the area percentage method with a correction factor added.

Images