Method for detecting impurities in lumepirone starting material LMS1

Abstract

The invention provides a method for detecting impurities in a lumepirone starting material LMS1, and belongs to the field of pharmaceutical analytical chemistry. The invention provides the method for detecting various impurities in the lumepirone starting material LMS1, the method can accurately quantify three isomers and three process impurities in the lumepirone starting material LMS1 at the same time, and the method is strong in specificity, high in sensitivity, good in accuracy, good in reproducibility, stable and reliable. By utilizing the method, the impurities can be controlled, and the safety of the lumepirone starting material LMS1 as a drug intermediate is ensured, so that the safety of a preparation of the lumepirone starting material LMS1 is further ensured, and the drug use risk is reduced. The method is suitable for laboratory research and development, and is also suitable for quality control of commercial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical analytical chemistry, and particularly relates to a method for detecting impurities in lumateperone starting material LMS1. Background Art

[0002] Lumateperone tosylate is a drug for oral treatment of adult schizophrenia. Lumateperone tosylate can coordinately regulate the transmission of serotonin, dopamine and glutamine, and thus play a therapeutic role.

[0003] Lumateperone starting material LMS1 (the compound name is ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate, molecular formula is C 14 H 17 BrN2O2, molecular weight is 325.21) is used as an intermediate in the synthesis of lumateperone. With the increasing requirements of regulatory agencies, the related substances of lumateperone starting material LMS1 need to be strictly controlled. According to the concept of Quality by Design (QBD), an effective detection method needs to be established for lumateperone starting material and strictly controlled. At present, there are no relevant patents or published literature reports on the detection method of related substances of (4aS,9 bR )-6-bromo-1,3,4,4 a ,5,9 b -hexahydro-2 H -pyrido[4,3- b indole-2-carboxylate.

[0004] The content of each impurity in the starting material lumateperone starting material LMS1 affects the quality of the final product. However, there is no relevant literature reporting the detection method of impurities in lumateperone starting material LMS1. It is necessary to develop a detection method to control the potential impurities in lumateperone starting material LMS1 to ensure the quality of the final product. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for detecting impurities in lumateperone starting material LMS1.

[0006] According to the synthesis route of lumateperone starting material LMS1, the present invention analyzes that the following impurities may be generated in the synthesis process, and the structures and related information are shown in Table 1.

[0007] Table 1 Structures and Related Information of Impurities in Lumateperone Starting Material To achieve the above invention purpose, the present invention provides the following technical solutions: The present invention provides a method for detecting impurities in lumateperone starting material LMS1, and the impurities include: , , , and ; the lumateperone starting material LMS1 is ; The method includes the following steps: (1) Prepare a test solution: Dissolve the lumateperone starting material LMS1 to be tested in a solvent to obtain a test solution; (2) Prepare a reference solution of lumateperone starting material LMS1; Dissolve the reference substance of lumateperone starting material LMS1 in a solvent to obtain a reference solution of lumateperone starting material LMS1; (3) Prepare a system suitability solution: Dissolve the reference substance of lumateperone starting material LMS1 and the impurity reference substance in a solvent to obtain a system suitability solution; (4) Perform liquid chromatography detection and calculate the content of impurities in the lumateperone starting material LMS1 to be tested; The chromatographic conditions include: Chromatographic column: Octadecylsilyl silica gel as the packing material; Mobile phase: Composed of mobile phase A and mobile phase B. Among them, mobile phase A is a phosphate solution with a pH of 2.2 - 2.4, and mobile phase B is one of methanol and acetonitrile or a mixed solution of methanol and acetonitrile. In the mixed solution, the ratio of methanol to acetonitrile is 20 - 80:100.

[0008] Furthermore, the chromatographic conditions also include: Chromatographic column: ODS - SP C18, 250 mm × 4.6 mm 5 μm; Mobile phase A: Phosphate solution with a pH of 2.25 - 2.35; Mobile phase B: Acetonitrile; Detector: Ultraviolet detector; Detection wavelength: 210 nm; Column temperature: 38 - 42 °C; Flow rate: 0.9 - 1.1 ml / min; Injection volume: 5 - 20 μl.

[0009] Furthermore, in the chromatographic conditions: The specification of the chromatographic column is 250 mm × 4.6 mm 5 μm; Mobile phase A: Phosphate solution with a pH of 2.3; The elution program is the following gradient elution: .

[0010] Further, the phosphate is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0011] Further, the concentration of the phosphate buffer solution is 0.01 mol / L to 0.05 mol / L, preferably 0.02 mol / L.

[0012] Further, the solvent is a mixed solution formed by an organic solvent and water. The organic solvent is one or more of methanol, ethanol, and acetonitrile, and the ratio of the organic solvent to water is 20 - 80:100; preferably, the solvent is a mixed solution formed by acetonitrile and water, and the ratio of acetonitrile to water is 50:50.

[0013] Further, the concentration of the lomepizole starting material LMS1 reference solution is 0.75 - 3 μg / ml; The concentration of the test solution is 0.25 - 1 mg / ml; In the system suitability solution, the concentration of the impurity reference is 0.5 μg / ml, and the concentration of the lomepizole starting material LMS1 reference is 0.5 mg / ml.

[0014] Further, the concentration of the lomepizole starting material LMS1 reference solution is 1.5 μg / ml; The concentration of the test solution is 0.5 mg / ml; In the system suitability solution, the concentration of the related impurity of the lomepizole starting material LMS1 is 0.3 - 0.7 μg / ml, and the concentration of the lomepizole starting material LMS1 is 0.3 - 0.7 mg / ml.

[0015] Further, the method for calculating the content of the impurity in the lomepizole starting material LMS1 to be measured is the external standard method for the main component, and the calculation method is: Impurity content (%) = Wherein, f represents the impurity correction factor; represents the peak area of the impurity in the test solution; represents the peak area of the lomepizole starting material LMS1 in the lomepizole starting material LMS1 reference solution; represents the concentration of the lomepizole starting material LMS1 in the lomepizole starting material LMS1 reference solution, μg / ml; V represents the dilution volume of the test solution, ml; M represents the weighed amount of the test sample, mg.

[0016] Further, the The correction factor is 0.63; The has a correction factor of 1.0; The has a correction factor of 1.0; The has a correction factor of 1.0; The has a correction factor of 1.0; The has a correction factor of 1.0.

[0017] The present invention has achieved the following beneficial effects: By selecting the chromatographic conditions, the present invention provides a liquid phase analysis method capable of simultaneously and accurately quantitatively detecting 6 impurities (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, and LMS1-Z13) in the starting material LMS1 of lumateperone. This method has strong specificity, high sensitivity, good accuracy, good reproducibility, and is stable and reliable. The detection method of the present invention can accurately detect the contents of the above-mentioned 6 impurities in the starting material LMS1 of lumateperone, control these impurities, ensure the safety of the starting material LMS1 of lumateperone as a drug intermediate, and further ensure the safety of its preparations, reducing the risk of medication. This method is applicable to laboratory research and development and also to the quality control of commercial production.

[0018] Obviously, based on the above content of the present invention, according to the common general knowledge and customary means in the art, without departing from the above basic technical idea of the present invention, various other forms of modification, substitution, or change can be made.

[0019] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. 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

[0020] Figure 1 It is the chromatogram of the blank solution in Example 1 of the present invention.

[0021] Figure 2 It is the chromatogram of the system suitability solution in Example 1 of the present invention.

[0022] Figure 3 It is the chromatogram of the test solution in Example 1 of the present invention.

[0023] Figure 4 It is the chromatogram of the system suitability solution and the LMS1-Z10 localization solution in Comparative Example 1 of the present invention.

[0024] Figure 5 Chromatogram of the system suitability solution for Comparative Example 2 of the present invention. Detailed implementation manners

[0025] The present invention discloses a liquid phase detection method for multiple impurities in lumateperone starting material LMS1. Those skilled in the art can draw on the content of this article and appropriately modify the parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through examples. It is obvious that relevant personnel can make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0026] "Room temperature" referred to in the present invention means 25 ± 10 °C.

[0027] Reagents or instruments used in the liquid phase detection method for multiple impurities in lumateperone starting material LMS1 provided by the present invention can all be purchased on the market.

[0028] Example 1. Liquid phase detection method for multiple impurities in lumateperone starting material LMS1 (1) Instrument: Shimadzu 2030 liquid chromatograph; (2) Chromatographic conditions: Using 0.02 mol / L potassium dihydrogen phosphate solution (adjusted to pH 2.3 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B, perform gradient elution according to the following table: Chromatographic column: ODS-SP C18, 250 mm × 4.6 mm, 5 μm; Detector: UV detector, detection wavelength 210 nm; Column temperature: 40 °C; Flow rate: 1.0 ml / min; Injection volume: 10 μl; (3) Preparation of blank solution: Take acetonitrile-water (50:50) as the blank solution.

[0029] (4) Preparation of reference solution: Take 10 mg of LMS1 reference substance, accurately weigh it, place it in a 100 ml volumetric flask, dissolve it with acetonitrile-water (50:50) and dilute to the mark, shake well; accurately measure 1.5 ml, place it in a 100 ml volumetric flask, and dilute to the mark with the solvent, shake well (obtain a reference solution with a concentration of 1.5 μg / ml).

[0030] (5) Preparation of test solution: Take 12.5 mg of the test sample of LMS1, accurately weigh it, place it in a 25-ml volumetric flask, dissolve it with acetonitrile-water (50:50) and dilute it to the mark, and shake well (to obtain a test sample solution with a concentration of 0.5 mg / ml).

[0031] (6) Preparation of the system suitability solution: Respectively take the impurity reference standards (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13) and the reference standard of the main component LMS1, accurately weigh them, dissolve them with acetonitrile-water (50:50) and quantitatively dilute to prepare a mixed solution containing 0.5 μg of each impurity and 0.5 mg of LMS1 per 1 ml as the system suitability solution.

[0032] (7) Impurity determination: Inject the above blank solution, reference solution, test sample solution and system suitability solution into the liquid chromatograph by direct injection, record the chromatogram, and calculate the content by the external standard method of the main component based on the peak area. The calculation formula is: Impurity content (%) = Where: A i : Peak area of the impurity in the test sample solution; A s : Peak area of LMS1 in the reference solution; C s : Concentration of LMS1 in the reference solution, μg / ml; V: Dilution volume of the test sample solution, ml; M: Sampling amount of the test sample, mg; For LMS1-Z4, f is 0.63, for LMS1-Z6, f is 1.0, for LMS1-Z10, f is 1.0, for LMS1-Z11, f is 1.0, for LMS1-Z12, f is 1.0, for LMS1-Z13, f is 1.0.

[0033] (8) Experimental results: Experimental results ( Figures 1 to 3It was shown that the blank solution had no interference, the peaks of each component in the system suitability solution were well separated, and the content was calculated by the external standard method of the main component based on the peak area. The test results of the test sample met the following criteria: LMS1-Z4 and LMS1-Z6 should not exceed 0.3%, LMS1-Z10, LMS1-Z11, LMS1-Z12, and LMS1-Z13 should not exceed 0.15%, the unknown impurities should not exceed 0.1%, and the total impurities should not exceed 1.0%.

[0034] The following uses the method of comparative examples to detect various impurities in lumateperone starting material LMS1.

[0035] Comparative Example 1. Detection method for various impurities in lumateperone starting material LMS1 Using the chromatographic conditions in the patent document: Method, Application and System for Determining the Impurity Content in Oral Disintegrating Tablets of Lumateperone Tosylate (Authorized Publication No. CN118566395 B), the detection of various impurities in lumateperone starting material LMS1 of the present invention was carried out.

[0036] (1) Instrument: Shimadzu 2030 liquid chromatograph; (2) Chromatographic conditions: Using 0.025 mol / L potassium dihydrogen phosphate solution (adjusted to pH 2.5 with phosphoric acid) as mobile phase A, and methanol-acetonitrile (50:50) as mobile phase B, gradient elution was carried out according to the following table: Chromatographic column: YMC-Pack Pro C18, 4.6 mm×150 mm, 3 μm; Detector: UV detector, detection wavelength 254 nm; Column temperature: 20 °C; Flow rate: 1.0 ml / min; Injection volume: 10 μl; (3) Preparation of solutions: Diluent: Acetonitrile-water (50:50); System suitability solution: Respectively take impurity reference substances (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13) and the main component LMS1 reference substance, dissolve with the diluent and quantitatively dilute to prepare a solution containing 5 μg of each impurity and 0.5 mg of LMS1 per 1 ml.

[0037] LMS1-Z10 Locating Solution: Accurately weigh 5.087 mg of the impurity LMS1-Z10 reference substance, place it in a 10-ml volumetric flask, dissolve it with the diluent and dilute it to the mark, and shake well. Pipette 50 μl of this solution, dissolve it with the diluent and dilute it to 5 ml, and shake well to obtain the solution.

[0038] (4)Detection: Precisely pipette 10 μl each of the system suitability solution and the LMS1-Z10 locating solution, inject them into the liquid chromatograph, and record the chromatogram.

[0039] (5)Experimental Results: The experimental results ( Figure 4 ) show that under the method conditions of the patent document (CN 118566395 B), LMS1-Z10 completely coincides with the main peak LMS1, and the resolution does not meet the requirements.

[0040] Comparative Example 2. Detection Method for Multiple Impurities in the Starting Material LMS1 of Lumateperone (1)Instrument: Shimadzu 2030 liquid chromatograph; (2)Chromatographic Conditions: Use 0.02 mol / L potassium dihydrogen phosphate solution (adjust the pH to 2.5 with phosphoric acid) as mobile phase A, and acetonitrile as mobile phase B, and perform gradient elution according to the following table: Chromatographic column: ODS-SP C18, 250 mm × 4.6 mm, 5 μm; Detector: Ultraviolet detector, detection wavelength 210 nm; Column temperature: 40 °C; Flow rate: 1.0 ml / min; Injection volume: 10 μl; (3)Preparation of the System Suitability Solution: Respectively take the impurity reference substances (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13) and the main component LMS1 reference substance, dissolve them with acetonitrile-water (50:50) and quantitatively dilute to prepare a solution containing 5 μg of each impurity and approximately 0.5 mg of LMS1 per 1 ml.

[0041] (4)Detection: Precisely pipette 10 μl of the system suitability solution, inject it into the liquid chromatograph, and record the chromatogram.

[0042] (5)Experimental Results: The experimental results ( Figure 5 ) show that the peaks of each impurity are relatively concentrated and relatively delayed, and the responses of each impurity are low, so the method is not applicable.

[0043] The following is the methodological verification of the present invention through experimental examples.

[0044] Experimental Example 1, Methodological Verification (1) Specificity Under the chromatographic conditions of Example 1, prepare the system suitability solution, blank solution, and test solution according to the method of Example 1. Respectively measure 10 μl of the system suitability solution, blank solution, and test solution, and inject them into the liquid chromatograph for detection. The liquid chromatogram is as Figures 1 to 3 shown. The blank solution does not interfere with the determination of each impurity, and the resolution between each component in the system suitability solution is not less than 1.5, with good resolution and meeting the requirements.

[0045] (2) Quantitation Limit and Detection Limit Stock solution of impurity LMS1-Z4 reference substance (1.5 mg / ml): Weigh accurately 15.181 mg of impurity LMS1-Z4 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0046] Stock solution of LMS1-Z6 reference substance (1.5 mg / ml): Weigh accurately 15.461 mg of LMS1-Z6 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0047] Stock solution of impurity LMS1-Z10 reference substance (0.5 mg / ml): Weigh accurately 5.087 mg of impurity LMS1-Z10 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0048] Stock solution of impurity LMS1-Z11 reference substance (0.5 mg / ml): Weigh accurately 5.310 mg of impurity LMS1-Z11 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0049] Stock solution of impurity LMS1-Z12 reference substance (0.5 mg / ml): Weigh accurately 5.288 mg of impurity LMS1-Z12 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0050] Stock solution of impurity LMS1-Z13 reference substance (0.5 mg / ml): Weigh accurately 12.283 mg of impurity LMS1-Z13 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0051] Stock solution of LMS1 reference substance (1.5 mg / ml): Weigh accurately 15.224 mg of LMS1 reference substance, place it in a 10 ml volumetric flask, dissolve and dilute to the mark with diluent, and shake well.

[0052] Dilute each reference substance stock solution step by step, inject and analyze according to the chromatographic conditions in Example 1, record the chromatogram, take the signal-to-noise ratio of about 10 as the quantitation limit and the signal-to-noise ratio of about 3 as the detection limit. The detection limit and quantitation limit results of each component are shown in Table 2.

[0053] Table 2 Quantitation Limit Results The experimental results show that the ratio of the concentration of the quantitation limit solution of each impurity to be measured to the limit concentration is not greater than 6.0%, and the signal-to-noise ratio is not less than 13.60; the ratio of the concentration of the detection limit solution of each impurity to be measured to the limit concentration is not greater than 3.0%, and the signal-to-noise ratio is not less than 3.01. The sensitivity meets the requirements.

[0054] (3) Linearity and Range Appropriately take the reference substance stock solutions of LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13 and LMS1 under the sensitivity item, dilute them with methanol to prepare a series of linear solutions, inject and analyze according to the chromatographic conditions in Example 1, record the chromatogram, take the injection concentration (μg / ml) as the abscissa (x) and the peak area as the ordinate (y), and perform linear regression. The results are shown in Table 3.

[0055] Table 3 Linear Relationship Results The results show that there is a good linear relationship between the main component and each impurity within the linear range of the quantitation limit to 200% of the limit.

[0056] (4) Repeatability Solvent: Acetonitrile - water (50:50).

[0057] Reference substance solution: Take the reference substance of lumateperone starting material LMS1, weigh it accurately, dissolve it with the solvent and quantitatively dilute it to prepare a solution containing about 1.5 μg per 1 ml.

[0058] Test solution: Take the test sample of LMS1, weigh it accurately, dissolve it with the solvent and quantitatively dilute it to prepare a solution containing about 0.5 mg per 1 ml, and prepare 6 parallel portions.

[0059] Take the above solutions, inject and analyze according to the chromatographic conditions in Example 1, record the chromatogram, calculate the content of each impurity by the external standard method of the main component based on the peak area, and the results are shown in Table 4.

[0060] Table 4 Repeatability Results The experimental results showed that 6 test solution samples were determined in parallel. The contents of each impurity were calculated by the external standard method of the main component with a correction factor. The detected amounts of each impurity to be measured all met the standards described in Example 1, and the RSDs of the detected amounts of each impurity to be measured were not greater than 4.4%, indicating that the repeatability met the requirements.

[0061] (5)Accuracy Diluent: Acetonitrile - water (50:50).

[0062] Test solution (base value): Refer to the data of "Repeatability".

[0063] Prepare 3 samples of 20%, 100%, and 150% spiked recovery solutions from each reference stock solution under the sensitivity item. Inject and analyze according to the chromatographic conditions in Example 1, record the chromatogram, and calculate the recovery rates of the impurities to be measured in each recovery solution by the external standard method for impurities; the results are shown in Table 5.

[0064] Table 5 Results of accuracy The experimental results showed that within the limit concentration range of 20% - 150% for each impurity to be measured, the recovery rates of each impurity were between 91.59% - 108.94%, and the RSDs were not greater than 4.2%, indicating that the accuracy met the requirements.

[0065] (6)Solution stability Take the reference solution and the test solution and place them at room temperature. Inject and analyze at different time intervals, record the chromatogram, and calculate the relative standard deviation of the peak areas or contents of each impurity in each solution. The test results are shown in Table 6.

[0066] Table 6 Results of solution stability The experimental results showed that the reference solution and the test solution were stable within 6 days when placed at room temperature.

[0067] (7)Robustness Diluent, system suitability solution, reference solution, and test solution: The same as those under "Repeatability".

[0068] Fine - tune the chromatographic method parameters according to Table 7. Inject and analyze the above - mentioned solutions respectively, record the chromatogram, and calculate the contents of each impurity by the external standard method of the main component. The results are shown in Table 8.

[0069] Table 7 Chromatographic parameters for robustness Table 8 Summary of robustness results The experimental results show that after minor changes in each chromatographic parameter (column temperature ±2 °C, flow rate ±0.1 ml / min, mobile phase pH ±0.05, chromatographic column and instrument), the solvent blank does not interfere with the detection of each impurity to be measured. The resolution between impurity peaks in the system suitability solution is not less than 1.2, and the resolution between the main component peak and the adjacent impurity is not less than 1.6. The detected amounts of each impurity to be measured in the test solution meet the requirements, and the RSDs are not greater than 8.9%. The method durability meets the requirements.

[0070] In summary, the method for determining impurities in the starting material LMS1 of lumateperone according to the present invention has strong specificity, high sensitivity, and good linearity, repeatability, accuracy, solution stability and durability.

[0071] In summary, the present invention provides a method for detecting impurities in the starting material LMS1 of lumateperone. This method can accurately quantify three isomers and three process impurities in the starting material LMS1 of lumateperone simultaneously, and has strong specificity, high sensitivity, good accuracy, good reproducibility and stable and reliable method. This method is applicable to laboratory research and development, and also applicable to quality control in commercial production.

[0072] Obviously, the above is only the preferred embodiment of the present invention, which is only an example clearly illustrating the present invention, rather than a limitation on the embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several other different forms of improvements and refinements can be made. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent improvements and substitutions made within the spirit and principle of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A method for detecting impurities in lumateperone starting material LMS1, characterized in that, The impurities include: , , , , and ; The lumateperone starting material LMS1 is ; The method includes the following steps: (1) Prepare the test solution: Dissolve the starting material LMS1 of lumateperone to be tested in a solvent to obtain the test solution; (2) Prepare the reference solution of the starting material LMS1 of lumateperone: Dissolve the reference substance of the starting material LMS1 of lumateperone in a solvent to obtain the reference solution of the starting material LMS1 of lumateperone; (3) Prepare the system suitability solution: Dissolve the reference substance of the starting material LMS1 of lumateperone and the reference substance of the impurity in a solvent to obtain the system suitability solution; (4) Perform liquid chromatography detection and calculate the content of impurities in the starting material LMS1 of lumateperone to be tested; The chromatographic conditions include: Chromatographic column: Octadecylsilane-bonded silica gel as the filler; Mobile phase: Composed of mobile phase A and mobile phase B. Among them, mobile phase A is a phosphate solution with a pH of 2.2 - 2.4, and mobile phase B is one of methanol and acetonitrile or a mixed solution of methanol and acetonitrile. In the mixed solution, the ratio of methanol to acetonitrile is 20 - 80:

100.

2. The method according to claim 1, characterized in that, The said chromatographic conditions also include: Chromatographic column: ODS-SP C18, 250 mm×4.6 mm 5 μm; Mobile phase A: Phosphate solution with a pH of 2.25 - 2.35; Mobile phase B: Acetonitrile; Detector: Ultraviolet detector; Detection wavelength: 210 nm; Column temperature: 38 - 42 °C; Flow rate: 0.9 - 1.1 ml / min; Injection volume: 5 - 20 μl.

3. The method according to claim 2, characterized in that, In the said chromatographic conditions: The specification of the chromatographic column is 250 mm×4.6 mm 5 μm; Mobile phase A: Phosphate solution with a pH of 2.3; The elution program is the following gradient elution: 。 4. The method according to claim 1, characterized in that, The said phosphate is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or disodium hydrogen phosphate.

5. The method according to claim 1, characterized in that, The concentration of the said phosphate buffer solution is 0.01 mol / L - 0.05 mol / L.

6. The method according to claim 1, characterized in that, The said solvent is a mixed solution formed by an organic solvent and water. The said organic solvent is one or more of methanol, ethanol, and acetonitrile. The ratio of the organic solvent to water is 20 - 80:

100.

7. The method according to claim 1, characterized in that, The concentration of the reference solution of the starting material LMS1 of lumateperone is 0.75 - 3 μg / ml; The concentration of the test solution is 0.25 - 1 mg / ml; In the said system suitability solution, the concentration of the reference substance of the impurity is 0.5 μg / ml, and the concentration of the reference substance of the starting material LMS1 of lumateperone is 0.5 mg / ml.

8. The method according to claim 7, characterized in that, The concentration of the reference solution of the starting material LMS1 of lumateperone is 1.5 μg / ml; The concentration of the test solution is 0.5 mg / ml; In the said system suitability solution, the concentration of the related impurity of the starting material LMS1 of lumateperone is 0.3 - 0.7 μg / ml, and the concentration of the starting material LMS1 of lumateperone is 0.3 - 0.7 mg / ml.

9. According to the method described in claim 1, wherein, The method for calculating the content of impurities in the starting material LMS1 of lumateperone to be tested is the external standard method for the main component, and the calculation method is: Impurity content (%) = Among them, f represents the impurity correction factor; represents the peak area of the impurity in the test solution; represents the peak area of lumateperone starting material LMS1 in the lumateperone starting material LMS1 reference solution; represents the concentration of lumateperone starting material LMS1 in the lumateperone starting material LMS1 reference solution, μg / ml; V represents the dilution volume of the test solution, ml; M represents the weighed amount of the test sample, mg.

10. According to the method described in claim 9, wherein, The correction factor is 0.63; The correction factor is 1.0; The correction factor is 1.0; The correction factor is 1.0; The correction factor is 1.0; The correction factor is 1.0.

Images