Method for detecting residual solvent benzene in ziprasidone hydrochloride bulk drug

Abstract

The invention relates to a method for detecting residual solvent benzene in a ziprasidone hydrochloride bulk drug. According to the detection method, dimethyl sulfoxide is used as a diluent, a 2.8 mol / L potassium hydroxide solution is used as a cosolvent, and a dimethyl sulfoxide solution of high-concentration ziprasidone hydrochloride can be completely dissolved under a high-temperature heating condition, so that the sensitivity of benzene meets the requirement; and detecting the benzene in the ziprasidone hydrochloride bulk drug by using a gas chromatograph (GC-FID headspace sampling) connected with a hydrogen flame ionization detector. The detection method can be used for quantitatively detecting benzene higher than 0.4 ppm in ziprasidone hydrochloride bulk drugs. The method is high in sensitivity and practicability, and the detection process is simple and rapid.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical analytical chemistry, and relates to a method for detecting residual solvent benzene in ziprasidone hydrochloride bulk drug, in particular to a method for detecting residual solvent benzene in ziprasidone hydrochloride bulk drug by using GC-FID headspace injection mode. Background Art

[0002] Ziprasidone hydrochloride is an atypical antipsychotic drug, also known as a new generation of antipsychotic drug, which was synthesized by Harry Howard of Pfizer in 1987. It has strong affinities for dopamine D2, D3, 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1D and α1 adrenergic receptors; and has a medium affinity for histamine H1 receptor. It has antagonistic effects on dopamine D1, D2, 5-HT2A, 5-HT1D and agonistic effect on 5-HT1A receptor. This product inhibits the reuptake of 5-HT and norepinephrine by the presynaptic membrane, and its blocking intensity is similar to that of risperidone and haloperidol, and is stronger than that of olanzapine, quetiapine and clozapine. It is mainly used for acute or chronic, initial or recurrent schizophrenia, and is effective for both negative and positive symptoms of schizophrenia. Especially, the effect on negative symptoms is better. It can reduce positive symptoms such as hallucinations, delusions, abnormal thinking and actions; and also improve negative symptoms such as monotonous mood and reduced volitional behavior.

[0003] The Chinese chemical name of ziprasidone hydrochloride is: 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2(1H)-indol-2-one hydrochloride monohydrate, and its structural formula is:

[0004] The presence of residual solvents in drugs will greatly affect the safety of drug use. Therefore, it is of great significance to effectively control the quality of bulk drugs and related preparations by establishing corresponding analytical methods.

[0005] However, in the process of drug research and development, there are more stringent limit regulations on the content of the first-class residual solvent benzene in drug quality. Therefore, it is particularly important to establish an analytical method for the first-class residual solvent benzene in bulk drugs. Summary of the Invention

[0006] In the quality research process of ziprasidone hydrochloride, residual solvent acetone is involved, and benzene is a recognized process impurity in acetone and belongs to a class of solvents with greater harm. If solvents such as acetone and toluene are used in the project, the risk of introducing benzene must be considered, and a determination method for benzene should be developed and controlled in the product.

[0007] The chemical structural formula of benzene is:

[0008] At present, there is no relevant report on the detection method of residual solvent benzene in ziprasidone hydrochloride API.

[0009] According to the requirements of "Determination of Residual Solvents, General Chapter 0861, Volume IV of Chinese Pharmacopoeia 2020 Edition" and "ICH Q3C", the limit of benzene is specified as 2 ppm.

[0010] The inventor of the present invention found that ziprasidone hydrochloride API has poor solubility in most common solvents, is insoluble in conventional solvents such as dichloromethane, water and absolute ethanol, and the maximum dissolution concentration in the universal solvent dimethyl sulfoxide or N,N-dimethylformamide or N-methylpyrrolidone or methanol or acetonitrile is about 10 mg / ml. The sensitivity of benzene analyzed by gas chromatography under such conditions is far too low to meet the basic requirements.

[0011] The present invention uses dimethyl sulfoxide as a diluent and 2.8 mol / L potassium hydroxide solution as a co-solvent, so that the dimethyl sulfoxide solution of 50 mg / ml high-concentration ziprasidone hydrochloride can be completely dissolved under the condition of high-temperature heating, and the solution is clear and transparent. The 2.8 mol / L potassium hydroxide solution can not only assist in dissolving the dimethyl sulfoxide solution of high-concentration ziprasidone hydrochloride, but also improve the sensitivity of benzene, and there is no by-product interfering with the detection of benzene. At the same time, sodium hydroxide solutions with multiple concentrations were studied and compared, and it was found that they were not as effective as the 2.8 mol / L potassium hydroxide solution, and they could not ensure the complete dissolution of the dimethyl sulfoxide solution of 50 mg / ml high-concentration ziprasidone hydrochloride under the condition of high-temperature heating.

[0012] The purpose of the present invention is to provide a detection method for accurately determining residual solvent benzene in ziprasidone hydrochloride API. This method can provide a reliable basis for the control of ziprasidone hydrochloride API, which is beneficial to ensuring the quality of ziprasidone hydrochloride API and its preparations.

[0013] The present invention provides a detection method for residual solvent benzene in ziprasidone hydrochloride API, and the detection method includes the following steps: (1) Preparation of 2.8 mol / L potassium hydroxide solution: Weigh about 31.42 g of potassium hydroxide, dissolve it in water and dilute it to 200 ml, shake well and set aside for use; (2) Preparation of blank solution: Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 ml headspace vial, cover the cap, seal and mix well, and set aside for use; (3) Preparation of reference solution: Weigh an appropriate amount of benzene, dissolve it with dimethyl sulfoxide and dilute it. Then accurately measure 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 ml headspace vial, cover the cap, seal and mix well, and set aside for use; (4)Preparation of test solution: Weigh an appropriate amount of the sample of ziprasidone hydrochloride to be tested, place it in a 20-ml headspace vial, accurately add 2.5 ml of dimethyl sulfoxide, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, mix well, and set aside for use. (5)Respectively, pipette equal volumes of the blank solution, reference solution, and test solution prepared in steps (2), (3), and (4) into the gas chromatograph, and record the chromatogram. Read the following information therefrom: the retention time of benzene and the peak area of the main peak of benzene; In the detection method provided by the present invention, the detection method further includes: (6)According to the information read in step (5), calculate the content of the residual solvent benzene by the external standard method based on the peak area; (7)The formula for calculating the peak area of benzene by the external standard method is: Content (ppm) = C 对照品 ×A 供试品 ×K 供试品 / A 对照品 / M 供试品 ×10 6 .

[0014] Wherein, A 供试品 is the peak area of benzene in the test solution; A 对照品 is the peak area of benzene in the reference solution; C 对照品 is the concentration of benzene in the reference solution, mg / ml; K 供试品 is the dilution factor of benzene in the test solution, ml; M 供试品 is the weighed amount of the sample to be tested in the test solution, mg.

[0015] According to the detection method described in the present invention, wherein the gas chromatography conditions include: Chromatographic column: medium polar capillary column Injection mode: headspace injection Detector: flame ionization detector (FID); Column temperature programming: initial temperature is 40 °C, maintained for 10 minutes, heated at a rate of 8 °C per minute to 120 °C, and then heated at a rate of 20 °C per minute to 250 °C, maintained for 8 minutes; Carrier gas nitrogen flow rate: 1.0 ml / min to 2.0 ml / min, preferably 1.5 ml / min; Flame ionization detector temperature: 200 °C to 300 °C, preferably 250 °C; Injection port temperature: 200 °C to 300 °C, preferably 250 °C; Split ratio: 0.5 - 5:1, preferably 0.5:1; Headspace equilibration time: 30 min; Headspace equilibration temperature: 100 °C; Headspace shaking: On.

[0016] Furthermore, according to the detection method of the present invention, in step (3), the concentration of the reference solution is: 0.02 μg / ml - 0.1 μg / ml, preferably 0.1 μg / ml.

[0017] Furthermore, according to the detection method of the present invention, in step (4), the concentration of the test solution is 10 mg / ml - 50 mg / ml, preferably 50 mg / ml.

[0018] Furthermore, according to the detection method of the present invention, the medium-polarity capillary column is Agilent DB-624 (30 m × 0.530 mm, 3.00 μm).

[0019] Furthermore, according to the detection method of the present invention, the headspace shaking magnitude is 8.

[0020] Furthermore, according to the detection method of the present invention, the cycle time is 42 min.

[0021] Furthermore, according to the detection method of the present invention, the temperature of the quantitative loop is 110 °C.

[0022] Even further, according to the detection method of the present invention, the temperature of the transfer line is 120 °C.

[0023] The present invention provides a method for detecting residual solvent benzene in ziprasidone hydrochloride raw material drug. By selecting specific chromatographic conditions, it can simply, rapidly, and accurately separate and detect the content of benzene in ziprasidone hydrochloride raw material drug, thereby ensuring the quality control of ziprasidone hydrochloride raw material drug and playing a guiding role in the development of the synthesis process.

[0024] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modification, substitution, or variation can be made.

[0025] The following further elaborates on the above content of the present invention through specific embodiments. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Description of the Drawings

[0026] Figure 1It represents the GC-FID headspace injection chromatogram of the blank solution for the specificity test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 1.

[0027] Figure 2 It represents the GC-FID headspace injection chromatogram of the reference solution for the specificity test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 1.

[0028] Figure 3 It represents the GC-FID headspace injection chromatogram of the test solution for the specificity test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 1.

[0029] Figure 4 It represents the GC-FID headspace injection chromatogram of the mixed solution for the specificity test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 1.

[0030] Figure 5 It represents the GC-FID headspace injection chromatogram of the quantitation limit solution for the quantitation limit test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 2.

[0031] Figure 6 It represents the GC-FID headspace injection chromatogram of the C-150% linear solution for the linearity and range test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 3.

[0032] Figure 7 It represents the GC-FID headspace injection chromatogram of the A-100% recovery solution for the accuracy test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 4.

[0033] Figure 8 It represents the GC-FID headspace injection chromatogram of the reference solution - 14h for the solution stability test of benzene as a residual solvent in the ziprasidone hydrochloride bulk drug of Example 5.

[0034] Figure 9 It represents the GC-FID headspace injection chromatogram of the benzene positioning solution for the sensitivity experiment of benzene using pure DMSO as a diluent to investigate the residual solvent benzene in the ziprasidone hydrochloride bulk drug of Comparative Example 1.

[0035] Figure 10 It represents the GC-FID headspace injection chromatogram of the benzene reference solution when the ratio of 2.5 mol / L potassium hydroxide solution to DMSO is 3:1.5 for the residual solvent benzene in the ziprasidone hydrochloride bulk drug of Comparative Example 2. Detailed implementation mode

[0036] The present invention is further illustrated by the following examples, but it should be understood that the following examples are not limited to the scope of the present invention. The reagents used in the following examples can be easily obtained from the market.

[0037] (1) Information on reagents, test drugs, samples and reference substances Ziprasidone hydrochloride API (Chongqing Liujiang Pharmaceutical Technology Co., Ltd., batch number: F01-23101801D); Benzene (Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: D1701034, chromatographically pure, content: ≥99.7%); Dimethyl sulfoxide (Honeywell, batch number: EC780-CN, chromatographic grade, content: >99.5%); Potassium hydroxide (Chengdu Kelong Chemical Co., Ltd., analytical grade, batch number: 20210303010, ≥90.0%); Methanol (Beijing Mairida Technology Co., Ltd., chromatographically pure, batch number: 023936, ≥99.9%); Anhydrous ethanol (Chengdu Norsch Technology Co., Ltd., chromatographic grade, batch number: 2023042001, ≥99.9%); Isopropyl alcohol (Beijing Mairida Technology Co., Ltd., chromatographically pure, batch number: 02211670, ≥99.9%); Tetrahydrofuran (Honeywell, chromatographic grade, batch number: W1FM1H, 99.981%); n-Butanol (GENERAL-REAGENT, analytical grade, batch number: P2359726, ≥99.5%); Toluene (Chengdu Kelong Chemical Co., Ltd., analytical grade, batch number: 2022081101, ≥99.5%); N,N-dimethylformamide (Honeywell, chromatographic grade, batch number: ED360-CN, >99.9%); Ethyl chloride (Beijing Bailingwei Technology Co., Ltd., reference substance, batch number: 221051309, 2 mg / ml methanol solution).

[0038] (2) Main instruments Gas chromatograph: Agilent 7890B+7697A; Electronic balance: XSE105DU.

[0039] (3) The detection method is based on the gas chromatography method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0521).

[0040] 1. Main technical parameters of gas chromatography Gas chromatograph: Agilent 7890B+7697A; detector: hydrogen flame ionization detector (FID); chromatographic column model: Agilent DB-624 (30m×0.530mm, 3.00μm); flow rate: 1.5ml / min; Sampling method: headspace sampling; Detector temperature: 250 °C; Injector temperature: 250 °C; Split ratio: 0.5:1; Temperature programming: Initial temperature is 40 °C, maintained for 10 minutes, heated at a rate of 8 °C per minute to 120 °C, then heated at a rate of 20 °C per minute to 250 °C, maintained for 8 minutes; Headspace equilibration time: 30 min; Cycle time is 42 min; Headspace shaking: 8; Headspace equilibration temperature: 100 °C; Quantitative loop temperature is 110 °C; Transfer line temperature is 120 °C; Diluent: dimethyl sulfoxide.

[0041] 2. Determination method (1) Solution preparation 2.8 mol / L potassium hydroxide solution: Weigh accurately 31.3656 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well, and it is ready; Blank solution: Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 ml headspace vial, cover it, seal it, and mix well, and it is ready; Methanol, ethanol, isopropanol, tetrahydrofuran, n-butanol, toluene, N,N-dimethylformamide positioning solutions: Accurately measure 0.1 ml of methanol, ethanol, isopropanol, tetrahydrofuran, n-butanol, toluene, and N,N-dimethylformamide respectively, place them in different 20 ml headspace vials, add 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution to each, cover it, seal it, and mix well, and they are ready; Chloroethane positioning solution: Take 1 ml of chloroethane reference substance (methanol solution at 2 mg / ml), place it in a 50 ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, as the chloroethane mother liquor; Accurately measure 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 ml headspace vial, cover it, seal it, and mix well, and it is ready; Reference substance solution: Weigh accurately 32.7 mg of benzene, place it in a 50 ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, as the benzene stock solution; Accurately measure 1.6 ml of the benzene stock solution, place it in a 100 ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, as the benzene mother liquor; Accurately measure 1.0 ml of the benzene mother liquor, place it in a 50 ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, accurately measure 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 ml headspace vial, cover it, seal it, and mix well, and it is ready; Test solution: Weigh accurately 252.1 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, accurately add 2.5 ml of dimethyl sulfoxide, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, and mix well to obtain the test solution; Mixed solution: Weigh accurately 251.0 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, accurately add 0.1 ml each of methanol, ethanol, isopropanol, tetrahydrofuran, n-butanol, toluene, N,N-dimethylformamide, 0.1 ml of the above-mentioned benzene mother liquor and 0.1 ml of the chloroethane mother liquor, 1.6 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, and mix well to obtain the mixed solution.

[0042] (2)Detection Inject the headspace of the above blank solution, each localization solution, reference solution, test solution and mixed solution, record the chromatogram, and the chromatogram is shown in Figures 1 to 4 . The results of each solution are shown in Table 1 and Table 2.

[0043] (3)Results It can be seen from Figure 1 that the blank solution does not interfere with the detection of benzene; It can be seen from Figure 2 that benzene elutes at about 16.0 min and there are no interfering peaks nearby; It can be seen from Figure 3 that there are no interfering peaks near the elution peak of benzene in the test solution; It can be seen from Figure 4 that there are no interfering peaks near the elution peak of benzene in the mixed solution.

[0044] It can be seen from Figure 4 that the resolution between each residual solvent peak and the benzene peak in the mixed solution is greater than 1.5.

[0045]

[0046] Table 2 Results of system suitability test in Example 1

[0047] 1. Main technical parameters of gas chromatography: The same as in Example 1.

[0048] 2. Determination method (1)Solution preparation 2.8 mol / L potassium hydroxide solution: Weigh accurately 31.3656 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; Blank solution: Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover the vial, seal it, and mix well to obtain the blank solution; Benzene mother liquor: Accurately weigh 32.7 mg of benzene, place it in a 50-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, and use it as the benzene stock solution; accurately measure 1.6 ml of the benzene stock solution, place it in a 100-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, and use it as the benzene mother liquor; Quantitation limit solution: Accurately measure 0.2 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, accurately measure 2.5 ml of it and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap it, seal it, and mix well to obtain.

[0049] (2)Detection Take the above blank solution and the quantitation limit solution for headspace injection, record the chromatogram, and the chromatogram is shown in Figure 5 . The results of the quantitation limit solution are shown in Table 3.

[0050] (3)Results From Figure 5 it can be seen that this method has high detection sensitivity and can quantitatively detect residual solvent benzene in ziprasidone hydrochloride raw material drug above 0.4 ppm.

[0051] Table 3 Results of quantitation limit experiment in Example 2

[0052] 1. Main technical parameters of gas chromatography: The same as in Example 1.

[0053] 2. Determination method (1)Solution preparation 2.8 mol / L potassium hydroxide solution: Accurately weigh 31.3656 g of potassium hydroxide, dissolve it with water and dilute to 200 ml, shake well to obtain; Blank solution: Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap it, seal it, and mix well to obtain; Benzene mother liquor: Accurately weigh 32.7 mg of benzene, place it in a 50-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, and use it as the benzene stock solution; accurately measure 1.6 ml of the benzene stock solution, place it in a 100-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, and use it as the benzene mother liquor; Quantitation limit solution: Accurately measure 0.2 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, accurately measure 2.5 ml of it and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap it, seal it, and mix well to obtain.

[0054] C-30% solution: Accurately measure 0.3 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well. Accurately measure 2.5 ml of this solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the solution.

[0055] C-50% solution: Accurately measure 0.5 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well. Accurately measure 2.5 ml of this solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the solution.

[0056] C-80% solution: Accurately measure 0.8 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well. Accurately measure 2.5 ml of this solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the solution.

[0057] C-100% solution: Accurately measure 1.0 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well. Accurately measure 2.5 ml of this solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the solution.

[0058] C-150% solution: Accurately measure 1.5 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well. Accurately measure 2.5 ml of this solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the solution.

[0059] (2) Detection Inject the above blank solution and each linear solution into the headspace sampler, and record the chromatogram. The typical chromatogram is shown in Figure 6 , and the linearity and range results are shown in Table 4.

[0060] (3) Results Table 4 Results of the linearity and range experiment in Example 3

[0061] The above results show that: within the range of 20% - 150% of the limit concentration of benzene, the linear regression equation is y = 244.45x + 1.6959, the correlation coefficient is 0.9995, and the percentage of the Y-axis intercept to the 100% response value is 3.4%; it shows that benzene has good linearity within the range of 0.042 μg / ml - 0.313 μg / ml.

[0062] 1. Main technical parameters of gas chromatography: the same as in Example 1 2. Determination method (1) Solution preparation 2.8 mol / L potassium hydroxide solution: Weigh accurately 31.3656 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain; Blank solution: Pipette accurately 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution into the same 20-ml headspace vial, cover with a cap, seal, and mix well to obtain; Benzene stock solution: Weigh accurately 32.7 mg of benzene, place it in a 50-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the benzene stock solution; Pipette accurately 1.6 ml of the benzene stock solution into a 100-ml volumetric flask, dilute to the mark with dimethyl sulfoxide, shake well to obtain the benzene mother solution; Reference solution: Pipette accurately 1.0 ml of the benzene mother solution into a 50-ml volumetric flask, dilute to the mark with dimethyl sulfoxide, shake well, pipette accurately 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution into the same 20-ml headspace vial, cover with a cap, seal, and mix well to obtain;

[0063] C-30% solution: Pipette accurately 0.3 ml of the benzene mother solution into a 50-ml volumetric flask, dilute to the mark with dimethyl sulfoxide, shake well, pipette accurately 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution into the same 20-ml headspace vial, cover with a cap, seal, and mix well to obtain;

[0064] C-50% solution: Pipette accurately 0.5 ml of the benzene mother solution into a 50-ml volumetric flask, dilute to the mark with dimethyl sulfoxide, shake well, pipette accurately 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution into the same 20-ml headspace vial, cover with a cap, seal, and mix well to obtain;

[0065] C-150% solution: Pipette accurately 1.5 ml of the benzene mother solution into a 50-ml volumetric flask, dilute to the mark with dimethyl sulfoxide, shake well, pipette accurately 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution into the same 20-ml headspace vial, cover with a cap, seal, and mix well to obtain;

[0066] Test sample background solution: Weigh accurately 252.1 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, add accurately 2.5 ml of dimethyl sulfoxide, mix well, then add accurately 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover with a cap, seal, and mix well to obtain; A-30% recovery solution: Weigh accurately 250.1 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, add accurately 2.5 ml of C-30% solution, mix well, then add accurately 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover with a cap, seal, and mix well to obtain; A - 50% Recovery Solution: Accurately weigh 250.5 mg of ziprasidone hydrochloride, place it in a 20 - ml headspace vial, accurately add 2.5 ml of C - 50% solution, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, and mix well to obtain the solution; A - 100% Recovery Solution: Accurately weigh 251.0 mg of ziprasidone hydrochloride, place it in a 20 - ml headspace vial, accurately add 2.5 ml of the reference solution, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, and mix well to obtain the solution; A - 150% Recovery Solution: Accurately weigh 253.4 mg of ziprasidone hydrochloride, place it in a 20 - ml headspace vial, accurately add 2.5 ml of C - 150% solution, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover the vial, seal it, and mix well to obtain the solution; (2)Detection Take the above - mentioned blank solution, reference solution, sample background solution, and each recovery solution for headspace injection, and record the chromatogram. The typical chromatogram is shown in Figure 7 , and the accuracy results are shown in Table 5.

[0067] (3)Results Table 5 Results of the accuracy experiment in Example 4

[0068] The above results show that the A - 30%, A - 50%, A - 100%, and A - 150% recoveries of benzene are 88.0%, 89.2%, 85.7%, and 87.3% respectively, all of which meet the range of 75% - 120% specified in the General Principles for Validation of Analytical Methods 9101 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition and ICH. Moreover, the RSD of each recovery rate is 1.65% which is less than 5.0%; the accuracy of this method is good.

[0069] 1. Main technical parameters of gas chromatography: The same as in Example 1 2. Determination method (1)Solution preparation 2.8 mol / L potassium hydroxide solution: Accurately weigh 31.3656 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; Blank solution: Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20 - ml headspace vial, cover the vial, seal it, and mix well to obtain the solution; Benzene stock solution: Accurately weigh 32.7 mg of benzene, place it in a 50-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, and use it as the benzene stock solution; accurately measure 1.6 ml of the benzene stock solution, place it in a 100-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, and use it as the benzene mother liquor; Reference solution: Accurately measure 1.0 ml of the benzene mother liquor, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, accurately measure 2.5 ml of it and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cover it, seal it, and mix well to obtain the reference solution.

[0070] (2)Detection Inject the headspace of the above blank solution and reference solution, and record the chromatogram. The typical chromatogram is shown in Figure 8 , and the stability results of the reference solution are shown in Table 6.

[0071] (3)Results Table 6 Results of the solution stability experiment in Example 5

[0072] The above results show that: the relative deviation between the peak areas of benzene in the reference solution at each time point within 14 h at room temperature and 0 h is less than 10.0%, and the RSD of the peak areas at each point between 0 h and 14 h is 2.01% which is less than 5.0%, indicating that it is relatively stable within 14 h at room temperature.

[0073] 1. Main technical parameters of gas chromatography: The same as in Example 1 2. Determination method (1)Solution preparation Blank solution: Accurately measure 5 ml of dimethyl sulfoxide, place it in a 20-ml headspace vial, cover it, seal it, and mix well to obtain the blank solution; Reference solution: Accurately weigh 25.8 mg of benzene, place it in a 100-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well, use it as the benzene stock solution; accurately measure 1 ml of the benzene stock solution, place it in a 50-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, use it as the benzene mother liquor; accurately measure 0.5 ml of the benzene mother liquor, place it in a 100-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, accurately measure 5 ml of it, place it in a 20-ml headspace vial, cover it, seal it, and mix well to obtain the reference solution; Benzene positioning solution: Accurately measure 5 ml of the benzene mother liquor, place it in a 20-ml headspace vial, cover it, seal it, and mix well to obtain the benzene positioning solution; Test solution: Accurately weigh 51.1 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, accurately add 5 ml of dimethyl sulfoxide, cover it, seal it, and mix well to obtain the test solution; Test sample spiked solution: Weigh precisely 52.8 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, precisely add 5 ml of the reference solution, cover the vial, seal it, and mix well to obtain the solution.

[0074] (2)Detection Inject the above blank solution, reference solution, test sample solution, and test sample spiked solution into the headspace sampler, and record the chromatogram. The typical chromatogram is shown in Figure 9 .

[0075] (3)Results The benzene main peak could not be identified in the chromatograms of the reference solution, test sample solution, and spiked test sample solution; it indicates that when pure DMSO is used as the diluent, the sensitivity of benzene is too low to enable detection; In the chromatogram of the benzene positioning solution (concentration about 5 μg / ml), the main peak area of benzene is about 165 pA*s. To reach the reference solution concentration (0.025 μg / ml), it still needs to be diluted 200 times, and the theoretical area is about 0.8 pA*s, which is too low, so detection cannot be carried out; Combined with the fact that ziprasidone hydrochloride is insoluble in conventional solvents such as dichloromethane, water, and absolute ethanol, and its maximum solubility concentration in the universal solvent dimethyl sulfoxide or N,N-dimethylformamide or N-methylpyrrolidone or methanol or acetonitrile is about 10 mg / ml, the sensitivity of benzene analyzed by gas chromatography under these conditions is far too low to meet the basic requirements.

[0076] 1. Main technical parameters of gas chromatography: The same as in Example 1 2. Determination method (1)Solution preparation 1.5 mol / L sodium hydroxide solution: Weigh precisely 12 g of sodium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; 2.5 mol / L sodium hydroxide solution: Weigh precisely 20 g of sodium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; 2.8 mol / L potassium hydroxide solution: Weigh precisely 31 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; 5.0 mol / L potassium hydroxide solution: Weigh precisely 56 g of potassium hydroxide, dissolve it in water and dilute to 200 ml, shake well to obtain the solution; Reference solution: Weigh precisely 32.7 mg of benzene, place it in a 50-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the benzene stock solution; Precisely measure 1.6 ml of the benzene stock solution, place it in a 100-ml volumetric flask, dilute it to the mark with dimethyl sulfoxide, shake well, and prepare it as follows: ①Accurately measure 2.5 ml of the reference solution and 2.5 ml of 1.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ②Accurately measure 2.5 ml of the reference solution and 2.5 ml of 2.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ③Accurately measure 2.5 ml of the reference solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ④Accurately measure 2.5 ml of the reference solution and 2.5 ml of 5.0 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ⑤Accurately measure 4.0 ml of the reference solution and 1.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ⑥Accurately measure 3.0 ml of the reference solution and 1.5 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; ⑦Accurately measure 3.0 ml of the reference solution and 2.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well to obtain the solution; Test solution: Accurately weigh 250 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, and prepare it in the following manner: ①Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 1.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well. Heat to boiling, and the sample cannot be completely dissolved; ②Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well. Heat to boiling, and the sample cannot be completely dissolved; ③Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well. Heat to boiling, and the sample is completely dissolved; ④Accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 5.0 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well. Heat to boiling, and the sample is completely dissolved; ⑤Accurately measure 4.0 ml of dimethyl sulfoxide and 1.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, and mix well. Heat to boiling, and the sample is completely dissolved; ⑥Precisely measure 3.0 ml of dimethyl sulfoxide and 1.5 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; ⑦Precisely measure 3.0 ml of dimethyl sulfoxide and 2.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; Test sample spiked solution: Weigh precisely 250 mg of ziprasidone hydrochloride, place it in a 20-ml headspace vial, and prepare it as follows: ①Precisely measure 2.5 ml of reference solution and 2.5 ml of 1.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is not completely dissolved; ②Precisely measure 2.5 ml of reference solution and 2.5 ml of 2.5 mol / L sodium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is not completely dissolved; ③Precisely measure 2.5 ml of reference solution and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; ④Precisely measure 2.5 ml of reference solution and 2.5 ml of 5.0 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; ⑤Precisely measure 4.0 ml of reference solution and 1.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; ⑥Precisely measure 3.0 ml of reference solution and 1.5 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; ⑦Precisely measure 3.0 ml of reference solution and 2.0 ml of 2.5 mol / L potassium hydroxide solution, place them in the same 20-ml headspace vial, cap, seal, mix well, heat to boiling, and the sample is completely dissolved; Blank solution: Prepare the blank solution in the same way.

[0077] (2)Detection Take the above blank solution, reference solution, test sample solution and test sample spiked solution for headspace injection, and record the chromatogram. The typical chromatogram is shown in Figure 10 。

[0078] (3)Results Using sodium hydroxide solutions with different concentrations as cosolvents cannot ensure the complete dissolution of high-concentration ziprasidone hydrochloride samples under high-temperature heating conditions; when using 2.8 mol / L potassium hydroxide solution as a cosolvent, 50 mg / ml ziprasidone hydrochloride samples can be completely dissolved under high-temperature heating conditions, and the benzene sensitivity and recovery rate are optimal when the ratio to DMSO is 1:1.

Claims

1. A method for detecting residual solvent benzene in ziprasidone hydrochloride raw material, characterized in that: Dimethyl sulfoxide was used as a diluent and 2.8 mol / L potassium hydroxide solution was used as a co-solvent; a gas chromatograph (GC-FID headspace injection) connected to a hydrogen flame ionization detector was used for detection.

2. The detection method according to claim 1, characterized in that: The steps include: (1) Prepare 2.8 mol / L potassium hydroxide solution: weigh about 31.42 g of potassium hydroxide, dissolve it in water and dilute it to 200 ml, shake well and set aside; (2) Prepare blank solution: accurately measure 2.5 ml of dimethyl sulfoxide and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place in the same 20 ml headspace bottle, cover, seal, mix well, and set aside; (3) Prepare the reference solution: Weigh an appropriate amount of benzene, add dimethyl sulfoxide to dissolve and dilute, accurately measure 2.5 ml and 2.5 ml of 2.8 mol / L potassium hydroxide solution, place in the same 20 ml headspace bottle, cover, seal, mix well, and set aside; (4) Prepare the test solution: weigh an appropriate amount of ziprasidone hydrochloride sample to be tested, place it in a 20 ml headspace bottle, accurately add 2.5 ml of dimethyl sulfoxide, mix well, then accurately add 2.5 ml of 2.8 mol / L potassium hydroxide solution, cover, seal, mix well, and set aside; (5) Take the blank solution, reference solution and test solution mentioned above respectively and inject them into the gas chromatograph for headspace sampling and determination.

3. The detection method according to claim 2, characterized in that Chromatographic conditions included: Chromatographic column: medium polarity capillary column Injection method: headspace injection Detector: flame ionization detector (FID); Column temperature program: initial temperature 40 °C, maintained for 10 min, increased to 120 °C at a rate of 8 °C per minute, then increased to 250 °C at a rate of 20 °C per minute, maintained for 8 min; Carrier gas nitrogen flow rate: 1.0 ml / min to 2.0 ml / min, preferably 1.5 ml / min; Hydrogen flame ionization detector temperature: 200°C to 300°C, preferably 250°C; Inlet temperature: 200°C to 300°C, preferably 250°C; Split ratio: 0.5-5:1, preferably 0.5:1; Headspace equilibration time: 30 min; Headspace equilibrium temperature: 100°C; Headspace Shake: On.

4. The detection method according to claim 2 or 3, characterized in that: In the step (3), the concentration of the reference solution is 0.02 μg / ml to 0.1 μg / ml, preferably 0.1 μg / ml.

5. The detection method according to claim 2 or 3, characterized in that: In the step (4), the concentration of the test solution is 10 mg / ml to 50 mg / ml, preferably 50 mg / ml.

6. The chromatographic conditions according to claim 3, characterized in that: The intermediate polarity capillary column is Agilent DB-624 (30m×0.530mm, 3.00μm).

7. The chromatographic conditions according to claim 3, characterized in that: The headspace shake size is 8.

8. The chromatographic conditions according to claim 3, characterized in that: The cycle time is 42 minutes.

9. The chromatographic conditions according to claim 3, characterized in that: The quantitative loop temperature is 110°C.

10. The chromatographic conditions according to claim 3, characterized in that: The transmission line temperature is 120°C.

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