Impurity analysis method for active pharmaceutical ingredients of lumepirone tosylate

Abstract

The invention discloses an impurity analysis method for active pharmaceutical ingredients of lumepirone tosylate, which comprises the following steps: separating impurities in the active pharmaceutical ingredients by using a high performance liquid chromatograph and taking an ammonium acetate-aqueous solution and a triethylamine-acetonitrile solution as mobile phases, the problems that an existing analysis method is insufficient in separation degree, limited in sensitivity and lack of method specificity can be effectively solved. The analysis method is high in separation degree, strong in specificity and high in accuracy, especially can effectively separate the lumepirone tosylate isomer impurity KT004-P01 in an active pharmaceutical ingredient sample, is easy to operate in steps, and can meet the requirements of research, development and production.

Description

Technical Field

[0001] The present invention relates to a liquid chromatography analysis method, and particularly to an impurity analysis method for an active pharmaceutical ingredient. Background Art

[0002] Lumateperone Tosilate was developed by Intra-Cellular Therapies Inc. (ITCI) in the United States. It is a multi-target antipsychotic drug, and its unique efficacy stems from the synergistic regulation of dopamine D1 receptor, 5-HT2A receptor and glutamatergic system. In December 2019, this drug was approved for marketing by the US FDA under the trade name, becoming the first innovative drug in the field of schizophrenia treatment, and subsequently expanding to the indication of bipolar disorder. As a small molecule salt drug, the toluenesulfonate form not only significantly improves solubility and bioavailability, but also its complex synthesis route brings severe challenges in impurity control.

[0003] The impurities of Lumateperone Tosilate mainly come from four aspects: First, there may be residual unreacted starting materials (such as Lumateperone base), intermediates, chiral isomers and condensation by-products in the synthesis process; Second, under the conditions of light, high temperature or hydrolysis, the active pharmaceutical ingredient may degrade to generate ring-opening products, oxidation products and other degradation impurities; Finally, due to the excessive introduction of toluenesulfonic acid or accidental combination with other counterions (such as sulfonates), salt-related impurities may be formed.

[0004] Due to the polycyclic fused structure and multiple chiral centers of Lumateperone Tosilate, the physical and chemical properties of various impurities are highly similar to those of the main component, and it is difficult to achieve effective separation by traditional chromatography methods. The currently disclosed methods for analyzing related substances of Lumateperone Tosilate have insufficient resolution, limited sensitivity and lack of method specificity, and fail to systematically distinguish the correlation between process impurities and degradation products, making it difficult to meet the requirements of ensuring drug quality and the safety and effectiveness of clinical medication. Summary of the Invention

[0005] Object of the Invention: The object of the present invention is to provide an analysis method for impurities contained in the active pharmaceutical ingredient of Lumateperone Tosilate with high resolution, strong specificity and high accuracy that meets the requirements of the Chinese Pharmacopoeia.

[0006] Technical Solution: The impurity analysis method for the active pharmaceutical ingredient of Lumateperone Tosilate according to the present invention, the impurities include:

[0007]

[0008] The method comprises the following steps:

[0009] (1) Prepare the sample solution of the active pharmaceutical ingredient of lumateperone tosilate to be tested;

[0010] (2) Set the parameters of the chromatographic conditions on a high-performance liquid chromatograph:

[0011] (21) Chromatographic column, a chromatographic column with octadecylsilyl-bonded silica gel packing as the stationary phase;

[0012] (22) Eluent, including mobile phase A and mobile phase B. Mobile phase A is an ammonium acetate-aqueous solution, and the concentration of ammonium acetate in the ammonium acetate-aqueous solution is 5 - 30 mM. Mobile phase B is a triethylamine-acetonitrile solution, and the mass percentage of triethylamine in the triethylamine-acetonitrile solution is 0.02 - 0.1%;

[0013] (23) Elution mode, the flow rate of the mobile phase is 0.5 - 1.5 mL / min, gradient elution:

[0014] At 0 min, the volume ratio of mobile phase A is 92 - 98%, and the volume ratio of mobile phase B is 2 - 8%,

[0015] At 10 min, the volume ratio of mobile phase A is 65 - 75%, and the volume ratio of mobile phase B is 25 - 35%,

[0016] At 20 min, the volume ratio of mobile phase A is 40 - 50%, and the volume ratio of mobile phase B is 50 - 60%,

[0017] At 40 min, the volume ratio of mobile phase A is 35 - 45%, and the volume ratio of mobile phase B is 55 - 65%,

[0018] At 50 min, the volume ratio of mobile phase A is 5 - 15%, and the volume ratio of mobile phase B is 85 - 95%,

[0019] At 60 min, the volume ratio of mobile phase A is 5 - 15%, and the volume ratio of mobile phase B is 85 - 95%,

[0020] At 60.1 min, the volume ratio of mobile phase A is 92 - 98%, and the volume ratio of mobile phase B is 2 - 8%,

[0021] At 65 min, the volume ratio of mobile phase A is 92 - 98%, and the volume ratio of mobile phase B is 2 - 8%;

[0022] (24) Elution column temperature, 28 - 40 °C;

[0023] (25) Detection wavelength, 230 - 242 nm;

[0024] (26) Injector temperature, 2 - 8 °C;

[0025] (3) Inject the sample solution to be tested into a high performance liquid chromatograph, analyze and record the chromatogram.

[0026] Preferably, in step 1, the preparation of the sample solution of the active pharmaceutical ingredient of lumateperone tosylate to be tested includes:

[0027] (11) Prepare a methanol - water solution;

[0028] (12) Add lumateperone tosylate, mix well to obtain a sample, and store it at 2 - 8 °C for later use.

[0029] Preferably, in step 11, the volume percentage of methanol in the methanol - water solution is 10 - 90%; in step 12, the concentration of the active pharmaceutical ingredient in the sample is 1 - 3 mg / mL.

[0030] Preferably, the chromatographic column with octadecylsilyl bonded silica gel packing as the stationary phase in step 21 is a Waters XBridge C18 chromatographic column, with a specification of 4.6×150 mm, 3 μm; in the continuous time interval in step 23, the volume ratio of mobile phase A to B changes linearly; the elution column temperature in step 24 is 28 - 32 °C; the detection wavelength in step 25 is 236 - 240 nm.

[0031] Preferably, in step 3, the volume of the sample injected into the high performance liquid chromatograph is 2 - 8 μL; the high performance liquid chromatograph includes an Agilent 1260 high performance liquid chromatograph equipped with an ultraviolet detector.

[0032] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages: 1. The method has high resolution, strong specificity and high accuracy. In particular, it can effectively separate the lumateperone tosylate isomer impurity KT004 - P01 in the active pharmaceutical ingredient sample, and can meet the needs of research and production; 2. The experimental steps of the method are easy to operate. Description of the Drawings

[0033] Figure 1 It is the chromatogram of the system suitability solution for the method described in Example 1;

[0034] Figure 2 It is the chromatogram of the limit of quantitation solution for the method described in Example 1;

[0035] Figure 3 It is the chromatogram of the blank solution for the method described in Example 2;

[0036] Figure 4 It is the chromatogram of the system suitability solution for the method described in Example 2;

[0037] Figure 5 It is the chromatogram of the limit of quantitation solution for the method described in Example 2;

[0038] Figure 6 Chromatogram of the test solution for the method described in Example 2;

[0039] Figure 7 Chromatogram of the system suitability solution for the method described in Comparative Example 1;

[0040] Figure 8 Chromatogram of the system suitability solution for the method described in Comparative Example 2. Detailed implementation manners

[0041] The technical solutions of the present invention will be further described below.

[0042] Example 1:

[0043] 1. Sample preparation

[0044] 1.1 Preparation of the system suitability sample of lumateperone tosylate: Take lumateperone tosylate, impurity KT004-M3, impurity KT004-M4-P06, impurity KT004-M4-P10, impurity KT004-M4-P11, impurity KT004-P01 and impurity KT004-P05, dissolve them in a 50% methanol-aqueous solution to obtain a mixed solution with a final concentration of 2 mg / mL of lumateperone tosylate and a final concentration of 3 μg / mL of each of the above impurities, as the system suitability sample;

[0045] 1.2 Preparation of the quantitation limit sample of lumateperone tosylate: Take lumateperone tosylate, impurity KT004-M3, impurity KT004-M4-P06, impurity KT004-M4-P10, impurity KT004-M4-P11, impurity KT004-P01 and impurity KT004-P05 respectively, dissolve them in a 50% methanol-aqueous solution to obtain a mixed solution with a concentration of 3 μg / mL for each of the above compounds; then dilute this mixed solution by 3 times as the quantitation limit sample;

[0046] 2. Set the parameters of the chromatographic conditions on an Agilent 1260 high performance liquid chromatograph equipped with a DAD detector:

[0047] The chromatographic column is a Waters XBridge C18 chromatographic column with a specification of 4.6×150 mm, 3 μm;

[0048] The eluent includes mobile phase A and mobile phase B. Mobile phase A is an ammonium acetate-aqueous solution with a concentration of ammonium acetate of 20 mM, and mobile phase B is a triethylamine-acetonitrile solution with a mass percentage of triethylamine of 0.05%;

[0049] The elution mode is gradient elution, and the flow rate of the mobile phase is 1.0 mL / min. The specific elution gradient is as follows:

[0050] Elution time (min) Phase A (%) Phase B (%) 0 95 5 10 70 30 20 45 55 40 40 60 50 10 90 60 10 90 60.1 95 5 65 95 5

[0051] The elution column temperature is 30 °C; the detection wavelength is 230 nm; the injector temperature is 6 °C

[0052] 3. Inject 5 μL of the tolonium chloride lumateperone system suitability sample and the quantitation limit sample to be tested into an Agilent 1260 high performance liquid chromatograph equipped with a DAD detector, and analyze and record the chromatogram.

[0053] The test results are as Figure 1 、 2 shown. The resolution between lumateperone isomer impurity KT004-P01 and tolonium chloride lumateperone meets the requirements (R≥1.5), but the baseline rises slowly when the proportion of the organic phase increases, the method sensitivity is low, and there is a detection risk.

[0054] Example 2:

[0055] 1. Sample preparation

[0056] 1.1. Prepare the tolonium chloride lumateperone system suitability sample: Take tolonium chloride lumateperone, impurity KT004-M3, impurity KT004-M4-P06, impurity KT004-M4-P10, impurity KT004-M4-P11, impurity KT004-P01 and impurity KT004-P05, dissolve them with 50% methanol-aqueous solution to obtain a mixed solution with a final concentration of tolonium chloride lumateperone of 2 mg / mL and a final concentration of each of the above impurities of 3 μg / mL as the system suitability sample;

[0057] 1.2. Prepare the tolonium chloride lumateperone quantitation limit sample: Take tolonium chloride lumateperone, impurity KT004-M3, impurity KT004-M4-P06, impurity KT004-M4-P10, impurity KT004-M4-P11, impurity KT004-P01 and impurity KT004-P05 respectively, dissolve them with 50% methanol-aqueous solution to obtain a mixed solution with a concentration of each of the above compounds of 3 μg / mL; then dilute this mixed solution by 3 times as the quantitation limit sample;

[0058] 1.3. Prepare the tolonium chloride lumateperone test sample: Take the tolonium chloride lumateperone of the same batch as in step 1.1, dissolve it with 50% methanol-aqueous solution to obtain a solution with a final concentration of tolonium chloride lumateperone of 2 mg / mL as the test sample;

[0059] 2. Set the parameters of the chromatographic conditions on an Agilent 1260 high performance liquid chromatograph equipped with a DAD detector:

[0060] The chromatographic column was a Waters XBridge C18 column, with a specification of 4.6×150 mm, 3 μm;

[0061] The eluent included mobile phase A and mobile phase B. Mobile phase A was an ammonium acetate - aqueous solution with the concentration of ammonium acetate being 20 mM, and mobile phase B was a triethylamine - acetonitrile solution with the mass percentage of triethylamine being 0.05%;

[0062] The elution method was gradient elution, and the flow rate of the mobile phase was 1.0 mL / min. The specific elution gradient was as follows:

[0063] Elution time (min) Phase A (%) Phase B (%) 0 95 5 10 70 30 20 45 55 40 40 60 50 10 90 60 10 90 60.1 95 5 65 95 5

[0064] The column temperature for elution was 30 °C; the detection wavelength was 238 nm; the injector temperature was 6 °C

[0065] 3. Inject 5 μL of the blank solution, the tolonium chloride lumateperone system suitability sample, the quantitation limit sample, or the test sample into the high - performance liquid chromatograph, and analyze and record the chromatogram.

[0066] The chromatogram of the blank solution was as Figure 3 shown, without interference peaks; the chromatogram of the system suitability solution was as Figure 4 shown, and the chromatogram of the quantitation limit solution was as Figure 5 shown. The resolution between the tolonium chloride lumateperone isomer impurity KT004 - P01 and tolonium chloride lumateperone met the requirements (R≥1.5), and the peak shapes of each impurity were good, and the peak areas of each impurity at the quantitation limit concentration could be effectively detected; the chromatogram of the test sample solution was as Figure 6 shown, and the resolution between the tolonium chloride lumateperone isomer impurity KT004 - P01 and tolonium chloride lumateperone was 2.2, meeting the requirements.

[0067] Example 3:

[0068] Perform a methodological verification on the parameters of Example 2, and the results are as follows:

[0069] 1. Specificity

[0070] The chromatogram of the blank solution was as Figure 6 shown, without interference; in the chromatogram of the system suitability solution, the resolutions of tolonium chloride lumateperone, impurity KT004 - M3, impurity KT004 - M4 - P06, impurity KT004 - M4 - P10, impurity KT004 - M4 - P11, impurity KT004 - P01, and impurity KT004 - P05 were as shown in the following table:

[0071] Component name Retention time (min) Resolution Impurity KT004-M3 10.881 - Impurity KT004-M4-P11 22.288 - Impurity KT004-M4-P10 24.017 8.55 Impurity KT004-P05 26.335 8.82 Lumateperone tosylate 27.498 4.53 Impurity KT004-P01 28.229 2.42 Impurity KT004-M4-P06 48.293 -

[0072] 2. Quantitation limit / Detection limit

[0073] 2.1 The results of the quantitative limit test for impurity KT004-M3 are shown in Table 1. Its concentration quantitative limit is 0.9900 μg / mL, equivalent to 0.0495% of the test sample concentration, S / N is 20.94, and the RSD of the peak area is 3.6%; the detection limit concentration is 0.4950 μg / mL, and S / N is 8.74;

[0074] Table 1 Results of the quantitative limit test for impurity KT004-M3

[0075]

[0076]

[0077] 2.2 The results of the quantitative limit test for impurity KT004-M4-P06 are shown in Table 2. Its quantitative limit concentration is 0.9888 μg / mL, equivalent to 0.0494% of the test sample concentration, S / N is 13.48, and the RSD of the peak area is 8.7%; the detection limit concentration is 0.4944 μg / mL, and S / N is 5.76;

[0078] Table 2 Results of the quantitative limit test for impurity KT004-M4-P06

[0079]

[0080] 2.3 The results of the quantitative limit test for impurity KT004-M4-P10 are shown in Table 3. Its quantitative limit concentration is 0.9866 μg / mL, equivalent to 0.0493% of the test sample concentration, S / N is 15.98, and the RSD of the peak area is 6.4%; the detection limit concentration is 0.4934 μg / mL, and S / N is 8.24;

[0081] Table 3 Results of the quantitative limit test for impurity KT004-M4-P10

[0082]

[0083] 2.4 The results of the quantitative limit test for impurity KT004-M4-P11 are shown in Table 4. Its quantitative limit concentration is 0.9885 μg / mL, equivalent to 0.0494% of the test sample concentration, S / N is 105.82, and the RSD of the peak area is 2.5%; the detection limit concentration is 0.4943 μg / mL, and S / N is 37.32;

[0084] Table 4 Results of the quantitative limit test for impurity KT004-M4-P11

[0085]

[0086] 2.5. The results of the quantitation limit test for impurity KT004-P01 are shown in Table 5. Its quantitation limit concentration is 0.9840 μg / mL, which is equivalent to 0.0492% of the test sample concentration. The S / N is 28.44, and the RSD of the peak area is 8.3%. The detection limit concentration is 0.4920 μg / mL, and the S / N is 12.22;

[0087] Table 5 Results of the quantitation limit test for impurity KT004-P01

[0088]

[0089] 2.6. The results of the quantitation limit test for impurity KT004-P05 are shown in Table 6. Its quantitation limit concentration is 0.9771 μg / mL, which is equivalent to 0.0489% of the test sample concentration. The S / N is 46.11, and the RSD of the peak area is 5.3%. The detection limit concentration is 0.4886 μg / mL, and the S / N is 17.8;

[0090] Table 6 Results of the quantitation limit test for impurity KT004-P05

[0091]

[0092] 2.7. The results of the quantitation limit test for lumateperone tosylate are shown in Table 7. Its quantitation limit concentration is 0.1530 μg / mL, which is equivalent to 0.0077% of the test sample concentration. The S / N is 21.71, and the RSD of the peak area is 10.4%. The detection limit concentration is 0.4886 μg / mL, and the S / N is 17.8;

[0093] Table 7 Results of the quantitation limit test for lumateperone tosylate

[0094]

[0095] 3. Linearity and range

[0096] 3.1. In the concentration range of 0.8503 - 5.6688 μg / mL for impurity KT004-M3, the linear equation is y = 12.3568x - 0.0979, the correlation coefficient r = 0.9954, and the deviation of the Y-axis intercept is 0.29%, where x represents the concentration of the target compound and y represents the peak area of the target compound;

[0097] Table 8 Results of the linearity test for KT004-M3

[0098]

[0099] 3.2. For the impurity KT004-M4-P06 in the concentration range of 0.9885 - 6.5900 μg / mL, the linear equation is y = 14.289x + 3.3975, the correlation coefficient r = 0.9978, and the deviation of the Y-axis intercept is 6.52%, where x represents the concentration of the target compound and y represents the peak area of the target compound;

[0100] Table 9 Results of the linearity test for KT004-M4-P06

[0101]

[0102] 3.3. For the impurity KT004-M4-P10 in the concentration range of 0.9817 - 6.5448 μg / mL, the linear equation is y = 7.6799x + 0.2502, the correlation coefficient r = 0.9979, and the deviation of the Y-axis intercept is 1.00%, where x represents the concentration of the target compound and y represents the peak area of the target compound;

[0103] Table 10 Results of the linearity test for KT004-M4-P10

[0104]

[0105]

[0106] 3.4. For the impurity KT004-M4-P11 in the concentration range of 0.9834 - 6.5560 μg / mL, the linear equation is y = 20.967x + 0.6496, the correlation coefficient r = 0.9995, and the deviation of the Y-axis intercept is 0.93%, where x represents the concentration of the target compound and y represents the peak area of the target compound;

[0107] Table 11 Results of the linearity test for KT004-M4-P11

[0108]

[0109] 3.5. For the impurity KT004-P01 in the concentration range of 0.9618 - 6.4120 μg / mL, the linear equation is y = 10.678x + 0.0034, the correlation coefficient r = 0.9966, and the deviation of the Y-axis intercept is 0.01%, where x represents the concentration of the target compound and y represents the peak area of the target compound;

[0110] Table 12 Results of the linearity test for KT004-P01

[0111]

[0112]

[0113] 3.6. In the concentration range of 0.9819 - 6.5460 μg / mL for the impurity KT004 - P05, the linear equation is y = 14.525x + 1.0509, the correlation coefficient r = 0.9986, and the deviation of the Y - axis intercept is 2.3%. Here, x represents the concentration of the target compound, and y represents the peak area of the target compound;

[0114] Table 13 Results of the linearity test for KT004 - P05

[0115]

[0116] 3.7. In the concentration range of 0.9279 - 6.1860 μg / mL for lumateperone tosylate, the linear equation is y = 27.409x + 1.8884, the correlation coefficient r = 0.9997, and the deviation of the Y - axis intercept is 2.7%. Here, x represents the concentration of the target compound, and y represents the peak area of the target compound;

[0117] Table 14 Results of the linearity test for lumateperone tosylate

[0118]

[0119] 4. Correction factor

[0120] Using lumateperone tosylate as the standard compound, the correction factor is calculated as the ratio of the slope of the main component regression line to the slope of the impurity regression line:

[0121] The correction factor of impurity KT004 - M3 is 2.15; the correction factor of impurity KT004 - M4 - P06 is 1.98; the correction factor of impurity KT004 - M4 - P10 is 3.60; the correction factor of impurity KT004 - M4 - P11 is 1.30; the correction factor of impurity KT004 - P01 is 2.51; the correction factor of impurity KT004 - P05 is 1.85.

[0122] Comparative Example 1:

[0123] 1. Prepare a system suitability sample of lumateperone tosylate: Take lumateperone tosylate, impurity KT004 - M3, impurity KT004 - M4 - P06, impurity KT004 - M4 - P10, impurity KT004 - M4 - P11, impurity KT004 - P01, and impurity KT004 - P05, dissolve them in a 50% methanol - aqueous solution to obtain a mixed solution with a final concentration of 1 mg / mL for lumateperone tosylate and 1.5 μg / mL for each of the above - mentioned impurities, which is used as the system suitability sample;

[0124] 2. Set the parameters of the chromatographic conditions on a Thermo Fisher Vanquish high - performance liquid chromatograph equipped with a VWD detector:

[0125] The chromatographic column is a Waters XBridge C18 chromatographic column with a specification of 4.6×150mm, 3μm;

[0126] The eluent includes mobile phase A and mobile phase B. Mobile phase A is an ammonium acetate - aqueous solution with the concentration of ammonium acetate being 20 mM, and mobile phase B is a triethylamine - acetonitrile solution with the mass percentage of triethylamine being 0.02%;

[0127] The elution method is gradient elution, the flow rate of the mobile phase is 1.0 mL / min, and the specific elution gradient is as follows:

[0128] Elution time (min) Phase A (%) Phase B (%) 0 95 5 10 70 30 30 20 80 30.1 95 5 35 95 5

[0129] The column temperature for elution is 30°C; the detection wavelength is 230 nm; the injector temperature is 6°C

[0130] 3. Inject 10 μL of the toluenesulfonic acid lumateperone system suitability sample to be tested into the liquid chromatograph, analyze and record the chromatogram.

[0131] The chromatogram of the system suitability solution is as Figure 7 shown. The resolution between the toluenesulfonic acid lumateperone isomer impurity KT004 - P01 and toluenesulfonic acid lumateperone does not meet the requirements (R≥1.5).

[0132] Comparative Example 2:

[0133] 1. Prepare the toluenesulfonic acid lumateperone system suitability sample: Take toluenesulfonic acid lumateperone, impurity KT004 - M3, impurity KT004 - M4 - P06, impurity KT004 - M4 - P10, impurity KT004 - M4 - P11, impurity KT004 - P01 and impurity KT004 - P05, dissolve them with a 50% methanol - aqueous solution to obtain a mixed solution with the final concentration of toluenesulfonic acid lumateperone being 1 mg / mL and the final concentration of each of the above impurities being 1.5 μg / mL as the system suitability sample;

[0134] 2. Set the parameters of the chromatographic conditions on a Thermo Fisher Vanquish high - performance liquid chromatograph equipped with a VWD detector:

[0135] The chromatographic column is a Waters XBridge C18 chromatographic column with a specification of 4.6×150mm, 3μm;

[0136] The eluent includes mobile phase A and mobile phase B. Mobile phase A is an ammonium acetate - aqueous solution with the concentration of ammonium acetate being 20 mM, and mobile phase B is a triethylamine - acetonitrile solution with the mass percentage of triethylamine being 0.05%;

[0137] The elution method is gradient elution, the flow rate of the mobile phase is 1.0 mL / min, and the specific elution gradient is as follows:

[0138] Elution time (min) Phase A (%) Phase B (%) 0 95 5 10 70 30 20 42 58 25 40 60 40 20 80 45 10 90 50 10 90 55 95 5

[0139] The elution column temperature is 30 °C; the detection wavelength is 230 nm; the injector temperature is 6 °C

[0140] 3. Inject 10 μL of the toluenesulfonic acid lumateperone system suitability sample to be tested into the liquid chromatograph, analyze and record the chromatogram.

[0141] The chromatogram of the system suitability solution is as Figure 8 shown. The resolution between the toluenesulfonic acid lumateperone isomer impurity KT004-P01 and toluenesulfonic acid lumateperone does not meet the requirements (R≥1.5), and the baseline rises significantly when the proportion of the organic phase increases.

Claims

1. A method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate, characterized in that: The impurities include: The method comprises the following steps: (1) preparing a sample solution of the active pharmaceutical ingredient of lumepirone tosylate to be tested; (2) Setting the parameters of chromatographic conditions on the HPLC: (21) a chromatographic column, a chromatographic column having an octadecylsilane bonded silica gel filler as the stationary phase; (22) an eluent comprising a mobile phase A and a mobile phase B, wherein the mobile phase A is an ammonium acetate-water solution, wherein the concentration of ammonium acetate in the ammonium acetate-water solution is 5-30 mM, and the mobile phase B is a triethylamine-acetonitrile solution, wherein the mass percentage of triethylamine in the triethylamine-acetonitrile solution is 0.02-0.1%; (23) Elution mode, mobile phase flow rate 0.5-1.5 mL / min, gradient elution: 0min, the volume ratio of mobile phase A is 92-98%, and the volume ratio of mobile phase B is 2-8%, 10min, mobile phase A volume ratio is 65-75%, mobile phase B volume ratio is 25-35%, 20min, mobile phase A volume ratio is 40-50%, mobile phase B volume ratio is 50-60%, 40min, mobile phase A volume ratio is 35-45%, mobile phase B volume ratio is 55-65%, 50min, mobile phase A volume ratio is 5-15%, mobile phase B volume ratio is 85-95%, 60min, mobile phase A volume ratio is 5-15%, mobile phase B volume ratio is 85-95%, 60.1min, the volume ratio of mobile phase A is 92-98%, the volume ratio of mobile phase B is 2-8%, 65min, mobile phase A volume ratio is 92-98%, mobile phase B volume ratio is 2-8%; (24) elution column temperature, 28-40°C; (25) Detection wavelength: 230-242 nm; (26) Injector temperature, 2-8°C; (3) Injecting the sample solution to be tested into a high performance liquid chromatograph, analyzing and recording the chromatogram.

2. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: In step 1, a sample solution of the active pharmaceutical ingredient of lumepirone tosylate to be tested is prepared, comprising: (11) preparing a methanol-water solution; (12) Add lumepirone tosylate, mix thoroughly to obtain a sample, and store at 2-8°C for later use.

3. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 2, characterized in that: In step 11, the volume percentage of methanol in the methanol-water solution is 10-90%.

4. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 2, characterized in that: In step 12, the concentration of the active pharmaceutical ingredient in the sample is 1-3 mg / mL.

5. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: The chromatographic column with octadecylsilane bonded silica gel filler as the stationary phase in step 21 is a Waters XBridge C18 chromatographic column with a specification of 4.6×150 mm and 3 μm.

6. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: During the continuous time intervals described in step 23, the volume ratio of mobile phase A to mobile phase B changes linearly.

7. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: The elution column temperature in step 24 is 28-32°C.

8. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: The detection wavelength in step 25 is 236-240 nm.

9. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: In step 3, the volume of the sample injected into the high performance liquid chromatograph is 2-8 μL.

10. The method for analyzing impurities in the active pharmaceutical ingredient of lumepirone tosylate according to claim 1, characterized in that: The high performance liquid chromatograph includes an Agilent 1260 high performance liquid chromatograph equipped with an ultraviolet detector.

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