Method for simultaneously detecting two organic silicon impurities in ziprasidone hydrochloride intermediate product

Abstract

The invention relates to a method for simultaneously detecting two organic silicon impurities in a ziprasidone hydrochloride intermediate product. According to the detection method, the two organic silicon impurities in the ziprasidone hydrochloride intermediate product are simultaneously detected by using a gas chromatographic method of a hydrogen flame ionization detector. The detection method not only can solve the problem that the two organic silicon impurities cannot be quantified without characteristic ultraviolet absorption under the condition of liquid chromatography, but also can control one of the organic silicon impurities not to be easily degraded and converted into the other organic silicon impurity under the condition of gas phase high temperature, thereby ensuring that the quality of the ziprasidone hydrochloride intermediate product is real and reliable. The method can be used for simultaneously and quantitatively detecting two organic silicon impurities higher than 0.02% in the ziprasidone hydrochloride intermediate product, and is high in sensitivity, good in separation degree, high in practicability and simple and rapid in detection process.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical analytical chemistry, and relates to a method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride, specifically to a method for simultaneously detecting two organosilicon impurities, triethylsilane and hexaethyldisiloxane, in the intermediate product of ziprasidone hydrochloride by means of direct injection using GC-FID. Background Art

[0002] Ziprasidone hydrochloride is currently the only atypical antipsychotic drug that inhibits the reuptake of both norepinephrine and 5-hydroxytryptamine (5-HT), and is also known as a new generation of antipsychotic drug. It is mainly used for the treatment of schizophrenia. It acts on a variety of neurotransmitter receptors, including 5-hydroxytryptamine receptor antagonists, dopamine D2, D3, D4, D5 receptor antagonists, etc., thereby regulating the balance of central neurotransmitters and achieving the effect of treating mental diseases such as schizophrenia.

[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 chemical structural formula is:

[0004] A synthetic route of ziprasidone hydrochloride monohydrate is as follows (Organic Process Research & Development 2008, 12, 1142–1145):

[0005] In the above synthetic route, the carbonyl group of chemical structure 1 is reduced with triethylsilane to obtain chemical structure 2, which is an intermediate product of ziprasidone hydrochloride. In this route, the process impurity triethylsilane inevitably exists in the intermediate product of ziprasidone hydrochloride. At the same time, the hydrolysis product of triethylsilane, triethylsilanol, will also introduce the by-product hexaethyldisiloxane. Their existence greatly affects the safety of drug use. Therefore, it is necessary to establish an analytical method for these two organosilicon impurities in the intermediate product of ziprasidone hydrochloride, which is of great significance for effectively controlling the quality of ziprasidone hydrochloride raw material drug and related preparation products. Summary of the Invention

[0006] Currently, no relevant reports have been retrieved on simultaneously detecting two organosilicon impurities, triethylsilane and hexaethyldisiloxane, in the intermediate product of ziprasidone hydrochloride.

[0007] Chinese Patent CN118706974A discloses an analytical method for the residue of hexaethyldisiloxane in oseltamivir phosphate drugs. This method uses a headspace sampler to pretreat the sample by heating and then detects it with a gas chromatograph. Triethylsilane is unstable under headspace heating conditions and is more likely to hydrolyze into triethylsilanol, and triethylsilanol will further dehydrate and condense into hexaethyldisiloxane, making it difficult to simultaneously detect triethylsilane and hexaethyldisiloxane.

[0008] In the present invention, the Chinese chemical name of the intermediate product of ziprasidone hydrochloride is: 5-(2-chloroethyl)-6-chloro-1,3-dihydroindol-2-(2 H )-one, and its chemical structural formula is Chemical Structure 2:

[0009] Triethylsilane, the chemical structural formula is:

[0010] Hexaethyldisiloxane, the chemical structural formula is:

[0011] The present invention provides a detection method that can accurately determine two organosilicon impurities, triethylsilane and hexaethyldisiloxane, in the intermediate product of ziprasidone hydrochloride at the same time. Since triethylsilane and hexaethyldisiloxane have no characteristic ultraviolet absorption under liquid chromatography conditions, quantitative analysis cannot be carried out by liquid chromatography. The detection method provided by the present invention includes: using an aprotic polar solvent as a diluent, which can not only ensure the complete dissolution of a certain concentration of the intermediate product of ziprasidone hydrochloride and meet the sensitivity requirements of the two organosilicon impurities, but also ensure that triethylsilane is not easily degraded into triethylsilanol under high-temperature gas phase conditions, thereby blocking the dehydration and condensation of triethylsilanol to form hexaethyldisiloxane, so that simultaneous detection can be carried out by gas chromatography with a flame ionization detector. This method does not use derivatization means, can save analysis time and consumable costs at the same time, can provide a reliable basis for the control of ziprasidone hydrochloride raw materials, and is conducive to ensuring the quality of ziprasidone hydrochloride raw materials and preparations.

[0012] The present invention provides a detection method for two organosilicon impurities in the intermediate product of ziprasidone hydrochloride, and this detection method includes the following steps: (1) Prepare a mixed reference solution: Weigh the reference substance of triethylsilane and the reference substance of hexaethyldisiloxane, place them in the same volumetric flask, add a diluent to dissolve and dilute to prepare a mixed reference solution; or, dissolve and dilute the reference substance of triethylsilane and the reference substance of hexaethyldisiloxane with a diluent respectively to obtain a reference solution of triethylsilane and a reference solution of hexaethyldisiloxane, and mix them to prepare a mixed reference solution; (2) Preparation of the test solution: Weigh the intermediate product of ziprasidone hydrochloride to be tested, place it in a volumetric flask, dissolve and dilute it with a diluent to prepare a test solution for use. (3) Separately pipette equal volumes of the mixed reference solution and the test solution from steps (1) and (2) into an FID gas chromatograph, and record the chromatogram; read the following information from it: the peak elution times of triethylsilane and hexaethyldisiloxane, and the peak areas of the main peaks of triethylsilane and hexaethyldisiloxane. Calculate the residual amounts of triethylsilane and hexaethyldisiloxane respectively by the external standard method based on the peak areas.

[0013] According to the detection method described in the present invention, wherein the diluent in steps (1) and (2) is N,N - Dimethylformamide.

[0014] According to the detection method described in the present invention, wherein the gas chromatography conditions include: Chromatographic column: Medium-polarity capillary column Injection mode: Direct injection Detector: Flame ionization detector (FID); Column temperature program: The initial temperature is 40°C ± 5°C, maintained for 8 minutes, heated at a rate of 8°C per minute to 120°C, then heated at a rate of 3°C per minute to 190°C, and then heated at a rate of 50°C per minute to 250°C, maintained for 20 minutes; Carrier gas nitrogen flow rate: 3.8 ml / min to 4.2 ml / min, preferably 4.0 ml / min; Flame ionization detector temperature: 295°C to 305°C, preferably 300°C; Injection port temperature: 295°C to 305°C, preferably 300°C; Split ratio: 0.5 to 2:1, preferably 2:1; Injection volume: 0.5 μl to 2 μl, preferably 1 μl.

[0015] Further, according to the detection method described in the present invention, in step (1), the concentration of the mixed reference solution: triethylsilane is 3.8 μg / ml to 38.2 μg / ml, preferably 20 μg / ml; hexaethyldisiloxane is 4.0 μg / ml to 195.8 μg / ml, preferably 100 μg / ml.

[0016] Further, according to the detection method described in the present invention, in step (2), the concentration of the test solution is 10 mg / ml to 20 mg / ml, preferably 20 mg / ml.

[0017] Further, according to the detection method of the present invention, in the gas chromatography conditions, the medium-polarity capillary column is GL Sciences Inert Cap 624 (30m×0.53mm, 3.00μm) or Agilent DB-624 (30m×0.530mm, 3.00μm).

[0018] The present invention provides a method for detecting two organosilicon impurities, triethylsilane and hexaethyldisiloxane, in an intermediate product of ziprasidone hydrochloride. By selecting specific chromatographic conditions and diluents, the contents of the two organosilicon impurities, triethylsilane and hexaethyldisiloxane, in the intermediate product of ziprasidone hydrochloride can be simply, quickly and accurately separated and detected, thus ensuring the controllable quality of the ziprasidone hydrochloride raw material drug and playing a guiding role in the development of the synthesis process.

[0019] 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 modifications, substitutions or changes can be made.

[0020] The following further detailed description is made on the above content of the present invention through specific embodiments. However, this should not be understood 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

[0021] Figure 1 It shows the chromatogram of the blank solution in the specificity experiment of the method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 1.

[0022] Figure 2 It shows the chromatogram of the triethylsilane localization solution in the specificity experiment of the method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 1.

[0023] Figure 3 It shows the chromatogram of the hexaethyldisiloxane localization solution in the specificity experiment of the method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 1.

[0024] Figure 4 It shows the chromatogram of the test solution in the specificity experiment of the method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 1.

[0025] Figure 5 It shows the chromatogram of the mixed solution in the specificity experiment of the method for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 1.

[0026] Figure 6 It represents the chromatogram of the detection limit solution in the experiment on the determination limit and detection limit of the methodological verification for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 2.

[0027] Figure 7 It represents the chromatogram of the determination limit solution in the experiment on the determination limit and detection limit of the methodological verification for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 2.

[0028] Figure 8 It represents the chromatogram of the C-150% linear solution in the experiment on linearity and range of the methodological verification for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 3.

[0029] Figure 9 It represents the chromatogram of the sample spiked solution in the experiment on accuracy & precision of the methodological verification for simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride in Example 4.

[0030] Figure 10 It represents that in Comparative Example 1, when simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride, methanol, dimethyl sulfoxide and N,N -dimethylformamide were used as diluents to investigate the solubility of ziprasidone hydrochloride and the specificity of triethylsilane and hexaethyldisiloxane - the chromatogram of the sample spiked solution under Condition 3 of ascending temperature.

[0031] Figure 11 It represents that in Comparative Example 2, when simultaneously detecting two organosilicon impurities in the intermediate product of ziprasidone hydrochloride, N,N -dimethylformamide was used as a diluent to adjust the temperature rising program for investigation - the chromatogram of the -dimethylformamide blank solution under Condition 2 of the temperature rising program. N,N -dimethylformamide blank solution chromatogram. Detailed implementation manner

[0032] 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.

[0033] (1) Information on reagents, test drugs, samples and reference substances Intermediate product of ziprasidone hydrochloride (API production base of Zhien Biotechnology Co., Ltd., batch number: M-M13A-B-B030-240501; 5-(2-chloroethyl)-6-chloro-1,3-dihydroindole-2-(2 H )-one); Triethylsilane (Shanghai Hanhong Technology Co., Ltd., batch number: BH-B14007-230720, content: 99.5%); Hexaethyldisiloxane (Shanghai Aladdin Biochemical Technology Co., Ltd., batch number: G22199524, content: 99.882%); N,N -Dimethylformamide (Honeywell, chromatographically pure, batch number: ED360-CN, >99.9%); Dimethyl sulfoxide (Honeywell, chromatographically pure, batch number: EB422-CN, >99.5%); Isopropanol (Beijing MRD Technology Co., Ltd., chromatographically pure, batch number: 02211670, ≥99.9%).

[0034] (2) Main instruments Gas chromatograph: Agilent 7890B + 7697A; Electronic balance: XSE105DU, XSE104.

[0035] (3) The detection method was determined by referring to the gas chromatography method (General Chapter 0521, Volume IV of the Chinese Pharmacopoeia 2020 Edition).

[0036] Example 1: Specificity experiment and system suitability experiment for simultaneous detection of two organosilicon impurities in the intermediate product of ziprasidone hydrochloride

[0037] 1. Main technical parameters of gas chromatography Gas chromatograph: Agilent 7890B + 7697A; Detector: Flame ionization detector (FID); Chromatographic column model: GL Sciences Inert Cap 624 (30m × 0.53mm, 3.00μm); Flow rate: 4.0ml / min; Injection mode: Direct injection; Injection volume: 1µl; Detector temperature: 300°C; Injection port temperature: 300°C; Split ratio: 2:1; Temperature programming: The initial temperature is 40°C, maintained for 8 minutes, heated at a rate of 8°C per minute to 120°C, then heated at a rate of 3°C per minute to 190°C, and then heated at a rate of 50°C per minute to 250°C, maintained for 20 minutes; Diluent: N,N -Dimethylformamide.

[0038] 2. Determination method (1) Solution preparation Blank solution: N,N -Dimethylformamide Triethylsilane positioning solution: Weigh accurately 20mg of triethylsilane, place it in a 100ml volumetric flask, add N,NDissolve in N,N-dimethylformamide, dilute to the mark, shake well to obtain the solution.

[0039] Hexaethyldisiloxane calibration solution: Weigh accurately 100 mg of hexaethyldisiloxane, place it in a 100 ml volumetric flask, add N, N N,N-dimethylformamide, dissolve and dilute to the mark, shake well to obtain the solution.

[0040] System suitability solution: Pipette accurately 2 ml each of the hexaethyldisiloxane calibration solution and the triethylsilane calibration solution into the same 20 ml volumetric flask, dilute to the mark with N,N N,N-dimethylformamide, shake well to obtain the solution.

[0041] Test solution: Weigh accurately 400 mg of the test substance, place it in a 20 ml volumetric flask, add N,N N,N-dimethylformamide, dissolve and dilute to the mark, shake well to obtain the solution.

[0042] Mixed solution: Weigh accurately 400 mg of the test substance, place it in a 20 ml volumetric flask, accurately add 2 ml each of the hexaethyldisiloxane calibration solution and the triethylsilane calibration solution, add N,N N,N-dimethylformamide, dissolve and dilute to the mark, shake well to obtain the solution.

[0043] (2)Detection Inject the above blank solution, each calibration solution, the system suitability solution, the test solution and the mixed solution directly, and record the chromatogram. The typical chromatogram is shown in Figures 1 to 5 , and the results of each solution are shown in Table 1 and Table 2.

[0044] (3)Results It can be seen from Figure 1 that the blank solution does not interfere with the detection of triethylsilane and hexaethyldisiloxane; It can be seen from Figure 2 that triethylsilane elutes at about 10.2 min and there are no interfering peaks nearby; It can be seen from Figure 3 that hexaethyldisiloxane elutes at about 27.6 min and there are no interfering peaks nearby; It can be seen from Figure 4 that there are no interfering peaks in the test solution near the elution peaks of triethylsilane and hexaethyldisiloxane; It can be seen from Figure 5 that there are no interfering peaks in the mixed solution near the elution peaks of triethylsilane and hexaethyldisiloxane.

[0045] Table 1 Results of the specificity experiment in Example 1

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

[0047] (4)Conclusion Neither the blank solution nor the test solution interfered with the detection of triethylsilane and hexaethyldisiloxane; the minimum resolution between triethylsilane and the adjacent peak in the mixed solution was 5.27, greater than 1.5; the minimum resolution between hexaethyldisiloxane and the adjacent peak was 1.61, greater than 1.5; and the peak area of the adjacent chromatographic peak accounted for less than 5% of the peak area of the reference solution, which could be ignored. This method had good specificity.

[0048] The system suitability solution was injected six times continuously. The RSD of the retention time of triethylsilane was 0.03%, less than 1.0%, and the RSD of the peak area was 0.93%, less than 10.0%; the RSD of the retention time of hexaethyldisiloxane was 0.01%, less than 1.0%, and the RSD of the peak area was 0.88%, less than 10.0%; this method had good system suitability.

[0049] Example 2: Experiment on the quantitative limit and detection limit of two organosilicon impurities in the intermediate product of ziprasidone hydrochloride

[0050] 1. Main technical parameters of gas chromatography: The same as in Example 1.

[0051] 2. Assay method (1)Solution preparation Blank solution: N,N -Dimethylformamide Triethylsilane stock solution: Weigh accurately 20 mg of triethylsilane, place it in a 100 ml volumetric flask, add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0052] Hexaethyldisiloxane stock solution: Weigh accurately 100 mg of hexaethyldisiloxane, place it in a 100 ml volumetric flask, add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0053] Quantitative limit solution: Accurately measure 1 ml of the triethylsilane stock solution and 0.2 ml of the hexaethyldisiloxane stock solution respectively, place them in the same 50 ml volumetric flask, and dilute to the mark with N,N -Dimethylformamide, shake well, and use it as the quantitative limit solution.

[0054] Detection limit solution: Accurately measure 3 ml of the quantitative limit solution, place it in a 10 ml volumetric flask, and dilute to the mark with N,N -Dimethylformamide, shake well, and use it as the detection limit solution.

[0055] (2)Detection Inject the above blank solution, limit of quantitation solution and limit of detection solution directly, and record the chromatogram. The typical chromatogram is shown in Figures 6 to 7 , the results of the limit of detection and limit of quantitation of triethylsilane are shown in Table 3, and the results of the limit of detection and limit of quantitation of hexaethyldisiloxane are shown in Table 4.

[0056] (3) Results From Figure 6 and Figure 7 it can be seen that this method has high detection sensitivity and can quantitatively detect the organosilicon impurities triethylsilane and hexaethyldisiloxane in the intermediate product of ziprasidone hydrochloride that are higher than 0.02%.

[0057] Table 3 Results of the limit of detection and limit of quantitation of triethylsilane in Example 2

[0058] Table 4 Results of the limit of detection and limit of quantitation of hexaethyldisiloxane in Example 2

[0059] (4) Conclusion The concentration of the triethylsilane limit of quantitation solution is 3.8 μg / ml, which is 19.1% of the limit concentration and 0.019% of the test sample concentration. The RSD of the peak area for 6 consecutive injections is 6.69%, and the signal-to-noise ratio is greater than 10; the detection limit concentration is 1.1 μg / ml, and the signal-to-noise ratio S / N for 3 consecutive injections is greater than 3; The concentration of the hexaethyldisiloxane limit of quantitation solution is 4.0 μg / ml, which is 4.0% of the limit concentration and 0.020% of the test sample concentration. The RSD of the peak area for 6 consecutive injections is 1.73%, and the signal-to-noise ratio is greater than 10; the detection limit concentration is 1.2 μg / ml, and the signal-to-noise ratio S / N for 3 consecutive injections is greater than 3; This method has good sensitivity.

[0060] 1. Main technical parameters of gas chromatography: the same as in Example 1.

[0061] 2. Assay method (1) Solution preparation Blank solution: N,N - Dimethylformamide Linear stock solution: Weigh accurately 20 mg of triethylsilane and 100 mg of hexaethyldisiloxane, place them in the same 100 ml volumetric flask, add N,N - Dimethylformamide to dissolve and dilute to the mark, shake well, and obtain.

[0062] Linear solution: Accurately measure the linear stock solution and prepare it with N,N - Dimethylformamide according to the following table.

[0063]

[0064] LOQ solution: Take the solution at the limit of quantitation under "Limit of Quantitation and Limit of Detection".

[0065] (2) Detection Inject the above blank solution and each linear solution directly, and record the chromatogram. The typical chromatogram is shown in Figure 8 , the results of the linearity and range experiment of triethylsilane are shown in Table 5, and the results of the linearity and range experiment of hexaethyldisiloxane are shown in Table 6.

[0066] (3) Results Table 5 Results of the linearity and range experiment of triethylsilane in Example 3

[0067] Table 6 Results of the linearity and range experiment of hexaethyldisiloxane in Example 3

[0068] (4) Conclusion In the concentration range of 3.8 μg / ml to 38.2 μg / ml, the linear regression equation of the concentration of triethylsilane and the peak area is y = 5.9975x - 5.2413, and the correlation coefficient r is 0.9995, which is greater than 0.995; the Y-axis intercept accounts for 4.57% of the 100% response value, which is less than 25%; In the concentration range of 4.0 μg / ml to 195.8 μg / ml, the linear regression equation of the concentration of hexaethyldisiloxane and the peak area is y = 3.9057x + 1.2335, and the correlation coefficient r is 0.9999, which is greater than 0.995; the Y-axis intercept accounts for 0.31% of the 100% response value, which is less than 25%; It shows that triethylsilane has good linearity in the concentration range of 3.8 μg / ml to 38.2 μg / ml, and hexaethyldisiloxane has good linearity in the concentration range of 4.0 μg / ml to 195.8 μg / ml.

[0069] 1. Main technical parameters of gas chromatography: The same as in Example 1 2. Determination method (1) Solution preparation Blank solution: N,N - Dimethylformamide Stock solution of reference substance: Weigh accurately 20 mg of triethylsilane and 100 mg of hexaethyldisiloxane, place them in the same 100 ml volumetric flask, add N,N - Dimethylformamide to dissolve and dilute to the mark, shake well, and you will get it. Prepare two portions in parallel.

[0070] Reference substance solution: Accurately measure 2 ml of the stock solution of reference substance, place it in a 20 ml volumetric flask, and useN,N Dilute to the scale with N,N-dimethylformamide, shake well, and you will get it. Prepare two portions in parallel.

[0071] Test solution: Weigh accurately 400 mg of the test substance, place it in a 20-ml volumetric flask, add N,N dissolve and dilute to the scale with N,N-dimethylformamide, shake well, and you will get it. Prepare two portions in parallel.

[0072] Spiked test solution: Weigh accurately 400 mg of the test substance, place it in a 20-ml volumetric flask, accurately add 2 ml of the reference stock solution, add N,N dissolve and dilute to the scale with N,N-dimethylformamide, shake well, and you will get it. Prepare six portions in parallel.

[0073] Note: The above solutions were prepared by two different experimenters at different times using different instruments for investigation.

[0074] (2)Detection Inject the above blank solution, reference solution, test solution and spiked test solution directly, and record the chromatogram. The typical chromatogram is shown in Figure 9 , and the accuracy & repeatability results are shown in Table 7, and the intermediate precision & precision are shown in Table 8 (3)Results Table 7 Results of accuracy & repeatability experiments in Example 4

[0075] Table 8 Results of intermediate precision & precision experiments in Example 4

[0076] (4)Conclusion In the repeatability and intermediate precision experiments, the recoveries of triethylsilane and hexaethyldisiloxane in 6 samples were 86.1% - 104.9%, and the maximum RSD of the recoveries was 4.75%; the recoveries of triethylsilane and hexaethyldisiloxane in 12 samples were 86.1% - 104.9%, and the maximum RSD of the recoveries was 5.25%; both met the requirements within the range of 80% - 120% specified in General Principles 9101 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition and ICH. The precision and accuracy of this method are both good.

[0077] 1. Main technical parameters of gas chromatography: The same as in Example 1 2. Assay method (1)Solution preparation Blank solution: N,N N,N-dimethylformamide Reference stock solution: Weigh accurately 20 mg of triethylsilane and 100 mg of hexaethyldisiloxane, place them in the same 100-ml volumetric flask, add N,N -dimethylformamide to dissolve and dilute to the mark, shake well, and you will get it.

[0078] Reference solution: Pipette accurately 2 ml of the reference stock solution, place it in a 20-ml volumetric flask, and dilute it to the mark with N,N -dimethylformamide, shake well, and you will get it.

[0079] Test sample spiked solution: Weigh accurately 400 mg of the test sample, place it in a 20-ml volumetric flask, accurately add 2 ml of the reference stock solution, and then add N,N -dimethylformamide to dissolve and dilute to the mark, shake well, and you will get it.

[0080] (2) Detection Inject the above blank solution, reference solution and test sample spiked solution directly, and record the chromatogram. The stability results of the reference solution are shown in Table 9, and the stability results of the test sample spiked solution are shown in Table 10.

[0081] (3) Results Table 9 Results of the stability experiment of the reference solution in Example 5

[0082] Table 10 Results of the stability experiment of the test sample spiked solution in Example 5

[0083] (4) Conclusion When the reference solution is placed at room temperature for 40 hours, the RSD of the peak areas of triethylsilane and hexaethyldisiloxane at each time point is less than 10%, but the peak area of triethylsilane decreases with the extension of time. When placed at room temperature for 20 hours, the relative deviation of its peak area from that at 0 hour is 9.26%, close to 10%; Test sample spiked solution: When placed at room temperature for 20 hours, the RSD of the peak areas of triethylsilane and hexaethyldisiloxane at each time point is less than 10%, but the peak area of triethylsilane decreases with the extension of time. When placed at room temperature for 40 hours, the relative deviation of its peak area from that at 0 hour is 15.96%, greater than 10%; Based on the above results, to ensure accurate results, the reference solution and the test sample solution should be injected within 9 hours at room temperature.

[0084] Comparative Example 1: Using methanol, dimethyl sulfoxide and N,N -dimethylformamide as diluents to investigate the solubility of ziprasidone hydrochloride and the specificity of triethylsilane and hexaethyldisiloxane 1. Main technical parameters of gas chromatography Gas chromatograph: Agilent 7890B + 7697A; Detector: Flame ionization detector (FID); Chromatographic column model: Agilent DB-624 (30m × 0.53mm, 3.00μm); Flow rate: 3.0 ml / min; Injection method: Direct injection; Injection volume: 1 μl; Detector temperature: 250 °C or 300 °C; Injection port temperature: 250 °C or 300 °C; Split ratio: 1:1 or 2:1 Temperature programming 1: Initial temperature is 40 °C, maintained for 8 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, held for 10 min; Temperature programming 2: Initial temperature is 40 °C, maintained for 8 minutes, heated at a rate of 8 °C per minute to 120 °C, then heated at a rate of 8 °C per minute to 225 °C, held for 5 min, then heated at a rate of 50 °C per minute to 250 °C, maintained for 30 minutes; Temperature programming 3: Initial temperature is 40 °C, maintained for 8 minutes, heated at a rate of 8 °C per minute to 120 °C, then heated at a rate of 3 °C per minute to 190 °C, held for 2 min, then heated at a rate of 50 °C per minute to 250 °C, maintained for 25 minutes.

[0085] Diluent: Methanol, dimethyl sulfoxide, N,N - Dimethylformamide.

[0086] 2. Assay method (1) Solution preparation Blank solution: Methanol, dimethyl sulfoxide, N,N - Dimethylformamide Test solution ①: Accurately weigh 100.2 mg of ziprasidone hydrochloride intermediate product, place it in a 20 ml headspace vial, accurately add 5 ml of dimethyl sulfoxide, cover and seal, shake well, and the solution is clear and transparent after shaking, and the sample is completely dissolved.

[0087] Test solution ②: Accurately weigh 102.6 mg of ziprasidone hydrochloride intermediate product, place it in a 20 ml headspace vial, accurately add 10 ml of methanol, cover and seal, shake, heat and sonicate, and the solution is still turbid, and the sample cannot be completely dissolved.

[0088] Test solution ③: Accurately weigh 100.0 mg of ziprasidone hydrochloride intermediate product, place it in a 20 ml headspace vial, accurately add N,N - Dimethylformamide 5 ml, cover and seal, shake well, and the solution is clear and transparent, and the sample is completely dissolved.

[0089] Triethylsilane calibration solution: Weigh accurately 19.2 mg of triethylsilane, place it in a 100-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the solution.

[0090] Hexaethyldisiloxane calibration solution: Weigh accurately 24.6 mg of hexaethyldisiloxane, place it in a 100-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the solution.

[0091] Test solution: Weigh accurately 200.5 mg of the test sample, place it in a 20-ml volumetric flask, dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the solution.

[0092] Fortified test solution: Weigh accurately 203.6 mg of the test sample, place it in a 20-ml volumetric flask, accurately add 1 ml each of the triethylsilane calibration solution and the hexaethyldisiloxane calibration solution, then dissolve it with dimethyl sulfoxide and dilute to the mark, shake well to obtain the solution.

[0093] (2) Detection Inject the above blank solution, each calibration solution, test solution ① and fortified test solution directly, and record the chromatogram. The typical chromatogram is shown in Figure 10 .

[0094] (3) Results When dimethyl sulfoxide is used as the diluent, under the conditions of temperature programming 1 - 3, there are unknown peaks interfering with hexaethyldisiloxane.

[0095] (4) Conclusion: The above results indicate that ziprasidone hydrochloride has poor solubility in methanol, good solubility in dimethyl sulfoxide and N, N - dimethylformamide, and the dissolution concentration is about 20 mg / ml; however, there are unknown peaks in the dimethyl sulfoxide blank solvent that interfere with hexaethyldisiloxane, and the specificity cannot meet the requirements.

[0096] Comparative Example 2: Using N,N - dimethylformamide as the diluent to adjust the temperature programming for investigation 1. Main technical parameters of gas chromatography Gas chromatograph: Agilent 7890B + 7697A; Detector: Flame ionization detector (FID); Chromatographic column model: GL Sciences Inert Cap 624 (30 m × 0.53 mm, 3.00 μm); Flow rate: 3.0 ml / min or 4.0 ml / min; Injection mode: Direct injection; Injection volume: 1 μl; Detector temperature: 250 °C or 300 °C; Injection port temperature: 250 °C or 300 °C; Split ratio: 1:1 or 2:1 Temperature programming 1: The initial temperature is 40°C, maintained for 8 minutes, heated at a rate of 8°C per minute to 120°C, then heated at a rate of 3°C per minute to 190°C, held for 2 min, and then heated at a rate of 50°C per minute to 250°C, maintained for 25 minutes.

[0097] Temperature programming 2: The initial temperature is 40°C, maintained for 8 minutes, heated at a rate of 8°C per minute to 120°C, then heated at a rate of 8°C per minute to 225°C, and then heated at a rate of 50°C per minute to 250°C, maintained for 25 minutes.

[0098] Temperature programming 3: The same as Example 1.

[0099] Diluent: N,N -Dimethylformamide

[0100] 2. Determination method (1) Solution preparation Blank solution: N,N -Dimethylformamide Triethylsilane positioning solution: Weigh accurately 19.3 mg of triethylsilane, place it in a 100 ml volumetric flask, add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0101] Hexaethyldisiloxane positioning solution: Weigh accurately 21.5 mg of hexaethyldisiloxane, place it in a 100 ml volumetric flask, add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0102] Test solution: Weigh accurately 200.8 mg of the test sample, place it in a 10 ml volumetric flask, add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0103] Test sample spiked solution: Weigh accurately 198.1 mg of the test sample, place it in a 10 ml volumetric flask, accurately add 1 ml each of the triethylsilane positioning solution and the hexaethyldisiloxane positioning solution, and then add N,N -Dimethylformamide to dissolve and dilute to the mark, shake well, and it is ready.

[0104] (2) Detection Inject the above blank solution, each positioning solution, test solution and test sample spiked solution directly, and record the chromatogram. The typical chromatogram is shown in Figure 11 .

[0105] (3) Results Use N,N- When N,N-dimethylformamide was used as the diluent, under the conditions of temperature programming 1 to 2, there were unknown peaks interfering with hexamethyldisiloxane. Under the conditions of temperature programming 3 (the same as in Example 1), N,N - The blank solution of N,N-dimethylformamide did not interfere with the detection of triethylsilane and hexamethyldisiloxane.

[0106] (4) Conclusion: The above results indicate that the chromatographic conditions in Examples 1 to 5 are optimal. Using N,N - N,N-dimethylformamide as the diluent can not only ensure the complete dissolution of a certain concentration of the intermediate product of ziprasidone hydrochloride, so that the sensitivities of the two organosilicon impurities meet the requirements, but also ensure that the specificity meets the requirements, thus ensuring the simultaneous detection of the two organosilicon impurities in the intermediate product of ziprasidone hydrochloride.

Claims

1. Method for simultaneously detecting two organosilicon impurities in intermediate product of ziprasidone hydrochloride, wherein, The chemical name of the intermediate product of ziprasidone hydrochloride is 5-(2-chloroethyl)-6-chloro-1,3-dihydroindol-2-(2 H )-one; the two organosilicon impurities are triethylsilane and hexaethyldisiloxane respectively; characterized in that the detection method comprises the following steps: (1) Prepare a mixed reference substance solution: Weigh the reference substances of triethylsilane and hexaethyldisiloxane, place them in the same volumetric flask, add N,N - dimethylformamide to dissolve and dilute to prepare a mixed reference substance solution; alternatively, dissolve and dilute the reference substances of triethylsilane and hexaethyldisiloxane with N,N - dimethylformamide respectively to obtain a triethylsilane reference substance solution and a hexaethyldisiloxane reference substance solution, and mix them to prepare a mixed reference substance solution; (2)Prepare the test solution: Weigh the intermediate product of ziprasidone hydrochloride to be tested, place it in a volumetric flask, add N,N -dimethylformamide to dissolve and dilute to prepare the test solution for use. (3) Respectively absorb the above equal amounts of the mixed reference solution and the test solution, and inject them into the FID gas chromatograph for injection and determination; Among them, the gas chromatography conditions include: Chromatographic column: medium-polarity capillary column Injection method: direct injection Detector: flame ionization detector (FID); Column temperature program: The initial temperature is 40°C ± 5°C, maintained for 8 minutes, heated at a rate of 8°C per minute to 120°C, then heated at a rate of 3°C per minute to 190°C, and then heated at a rate of 50°C per minute to 250°C, maintained for 20 minutes; Carrier gas nitrogen flow rate: 3.8 ml / min to 4.2 ml / min; Flame ionization detector temperature: 295°C to 305°C; Injection port temperature: 295°C to 305°C; Split ratio: 0.5 to 2:1; Injection volume: 0.5 μl to 2 μl.

2. The detection method according to claim 1, characterized in that: In the step (1) described above, the concentration of the mixed reference solution: triethylsilane is 3.8 μg / ml to 38.2 μg / ml; hexaethyldisiloxane is 4.0 μg / ml to 195.8 μg / ml.

3. The detection method according to claim 1, wherein: In the step (1) described above, the concentration of the mixed reference solution: triethylsilane is 20 μg / ml; hexaethyldisiloxane is 100 μg / ml.

4. The detection method according to any one of claims 1 to 3, characterized in that: In the step (2) described above, the concentration of the test solution is 10 mg / ml to 20 mg / ml.

5. The detection method according to claim 4, wherein: In the step (2) described above, the concentration of the test solution is 20 mg / ml.

6. The detection method according to any one of claims 1 to 3, characterized in that: In the gas chromatography conditions described above, Carrier gas nitrogen flow rate: 4.0 ml / min; and / or Flame ionization detector temperature: 300°C; and / or Injection port temperature: 300°C; and / or Split ratio: 2:1; and / or Injection volume: 1 μl.

7. The chromatographic conditions according to any one of claims 1 to 3, characterized in that: The medium-polarity capillary column is GL Sciences Inert Cap 624 (30 m × 0.53 mm, 3.00 μm) or Agilent DB-624 (30 m × 0.530 mm, 3.00 μm).

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