A method for detecting impurities in lumateperone starting material LMS1

Abstract

The present invention provides a method for detecting impurities in lomepirlone starting material LMS1, belonging to the field of pharmaceutical analytical chemistry. The present invention provides a method for detecting multiple impurities in lomepirlone starting material LMS1. This method can accurately quantify three isomers and three process impurities in lomepirlone starting material LMS1 simultaneously, and has strong specificity, high sensitivity, good accuracy, good reproducibility and stable and reliable method. Using this method, the control of these impurities can be achieved, ensuring the safety of lomepirlone starting material LMS1 as a pharmaceutical intermediate, thereby further ensuring the safety of its preparations and reducing the risk of medication. This method is applicable to laboratory research and development, and is also applicable to quality control in 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 then play a therapeutic role.

[0003] Lumateperone starting material LMS1 (the chemical name of the compound is ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate, molecular formula C 14 H 17 BrN2O2, molecular weight 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 publicly reported literature on the detection method of related substances of ethyl (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

[0008]

[0009] To achieve the above-mentioned invention object, the present invention provides the following technical solutions:

[0010] The present invention provides a method for detecting impurities in lomepizolam starting material LMS1, and the impurities include: , , , and ; The lomepizolam starting material LMS1 is ;

[0011] The method includes the following steps:

[0012] (1) Prepare a test solution: Dissolve the lomepizolam starting material LMS1 to be tested in a solvent to obtain a test solution;

[0013] (2) Prepare a reference solution of lomepizolam starting material LMS1; Dissolve the reference substance of lomepizolam starting material LMS1 in a solvent to obtain a reference solution of lomepizolam starting material LMS1;

[0014] (3) Prepare a system suitability solution: Dissolve the reference substance of lomepizolam starting material LMS1 and the reference substance of the impurity in a solvent to obtain a system suitability solution;

[0015] (4) Perform liquid chromatography detection and calculate the content of impurities in the lomepizolam starting material LMS1 to be tested;

[0016] The chromatographic conditions include:

[0017] Chromatographic column: Octadecylsilane chemically bonded silica gel as the filler;

[0018] 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.

[0019] Further, the chromatographic conditions also include: [[ID= forty-eight]] [[ID= forty-nine]]

[0020] Chromatographic column: ODS-SP C18, 250 mm × 4.6 mm 5 μm;

[0021] Mobile phase A: Phosphate solution with a pH of 2.25 - 2.35;

[0022] Mobile phase B: Acetonitrile;

[0023] Detector: Ultraviolet detector;

[0024] Detection wavelength: 210 nm;

[0025] Column temperature: 38 - 42 °C;

[0026] Flow rate: 0.9 - 1.1 ml / min;

[0027] Injection volume: 5 - 20 μl.

[0028] Furthermore, in the chromatographic conditions:

[0029] The specification of the chromatographic column is 250 mm × 4.6 mm 5 μm;

[0030] Mobile phase A: Phosphate solution with a pH of 2.3;

[0031] The elution program is the following gradient elution:

[0032] .

[0033] Furthermore, the phosphate is potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate or disodium hydrogen phosphate.

[0034] Furthermore, the concentration of the phosphate buffer solution is 0.01 mol / L - 0.05 mol / L, preferably 0.02 mol / L.

[0035] Furthermore, 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. 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.

[0036] Furthermore, the concentration of the lomepirlone starting material LMS1 reference solution is 0.75 - 3 μg / ml;

[0037] The concentration of the test solution is 0.25 - 1 mg / ml;

[0038] In the system suitability solution, the concentration of the impurity reference is 0.5 μg / ml, and the concentration of the lomepirlone starting material LMS1 reference is 0.5 mg / ml.

[0039] Furthermore, the concentration of the lomepirlone starting material LMS1 reference solution is 1.5 μg / ml;

[0040] The concentration of the test solution is 0.5 mg / ml;

[0041] In the system suitability solution, the concentration of the related impurity of lomepirlone starting material LMS1 is 0.3 - 0.7 μg / ml, and the concentration of lomepirlone starting material LMS1 is 0.3 - 0.7 mg / ml.

[0042] Furthermore, the method for calculating the content of impurities in the lomepirlone starting material LMS1 to be tested is the external standard method for the main component, and the calculation method is as follows:

[0043] Impurity content (%) =

[0044] Wherein, f represents the impurity correction factor; represents the peak area of the impurity in the test solution; represents the peak area of lomepirlone starting material LMS1 in the reference solution of lomepirlone starting material LMS1; represents the concentration of lomepirlone starting material LMS1 in the reference solution of lomepirlone starting material LMS1, μg / ml; V represents the dilution volume of the test solution, ml; M represents the weighed amount of the test sample, mg.

[0045] Furthermore, the correction factor is 0.63;

[0046] The correction factor is 1.0;

[0047] The correction factor is 1.0;

[0048] The correction factor is 1.0;

[0049] The correction factor is 1.0;

[0050] The correction factor is 1.0.

[0051] The present invention has achieved the following beneficial effects:

[0052] Through the selection of chromatographic conditions, the present invention provides a liquid phase analysis method capable of accurately and simultaneously quantifying six impurities (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, and LMS1-Z13) in lumateperone starting material LMS1. 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 six impurities in lumateperone starting material LMS1, control these impurities, ensure the safety of lumateperone starting material LMS1 as a pharmaceutical intermediate, thereby further ensuring the safety of its preparations and reducing the medication risk. This method is applicable to laboratory research and development, and is also applicable to quality control in commercial production.

[0053] 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 modifications, substitutions, or changes can be made.

[0054] 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

[0055] Figure 1 It is the chromatogram of the blank solution in Example 1 of the present invention.

[0056] Figure 2 It is the chromatogram of the system suitability solution in Example 1 of the present invention.

[0057] Figure 3 It is the chromatogram of the test solution in Example 1 of the present invention.

[0058] 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.

[0059] Figure 5 It is the chromatogram of the system suitability solution in Comparative Example 2 of the present invention. Detailed Description of the Invention

[0060] The present invention discloses a liquid-phase detection method for various 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. Relevant personnel can obviously make changes or appropriate alterations 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.

[0061] As used in the present invention, "room temperature" means 25 ± 10 °C.

[0062] The reagents or instruments used in the liquid-phase detection method for various impurities in lumateperone starting material LMS1 provided by the present invention can all be purchased on the market.

[0063] Example 1. Liquid-phase detection method for various impurities in lumateperone starting material LMS1

[0064] (1) Instrument: Shimadzu 2030 liquid chromatograph;

[0065] (2) Chromatographic conditions:

[0066] 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, gradient elution is carried out according to the following table:

[0067]

[0068] Chromatographic column: ODS-SP C18, 250 mm × 4.6 mm, 5 μm;

[0069] Detector: UV detector, detection wavelength 210 nm;

[0070] Column temperature: 40 °C;

[0071] Flow rate: 1.0 ml / min;

[0072] Injection volume: 10 μl;

[0073] (3) Preparation of blank solution: Take acetonitrile-water (50:50) as the blank solution.

[0074] (4) Preparation of reference solution:

[0075] Take 10 mg of LMS1 reference substance, weigh accurately, 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, dilute to the mark with the solvent, and shake well (to obtain a reference solution with a concentration of 1.5 μg / ml).

[0076] (5) Preparation of test solution:

[0077] Take 12.5 mg of LMS1 test substance, weigh accurately, place it in a 25 ml volumetric flask, dissolve it with acetonitrile-water (50:50) and dilute to the mark, shake well (to obtain a test solution with a concentration of 0.5 mg / ml).

[0078] (6) Preparation of system suitability solution:

[0079] Respectively take impurity reference substances (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13) and the LMS1 reference substance of the main component, weigh accurately, 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.

[0080] (7) Impurity determination:

[0081] Inject the above blank solution, reference solution, test 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:

[0082] Impurity content (%) =

[0083] Where: A i : Peak area of the impurity in the test solution;

[0084] A s : Peak area of LMS1 in the reference solution;

[0085] C[[ID=z6]] s : Concentration of LMS1 in the reference solution, μg / ml;

[0086] V: Dilution volume of the test solution, ml;

[0087] M: Sampling amount of the test substance, mg;

[0088] For LMS1-Z4 f is 0.63, for LMS1-Z6 f is 1.0, for LMS1-Z10 fis 1.0, for LMS1-Z11 f is 1.0, for LMS1-Z12 f is 1.0, for LMS1-Z13 f is 1.0.

[0089] (8) Experimental results:

[0090] The experimental results ( Figures 1 - 3 ) show that the blank solution has no interference, the separation between the peaks of each component in the system suitability solution is good. Calculating the content by the external standard method of the main component based on the peak area, the test results of the test sample meet the following standards: the contents of LMS1-Z4 and LMS1-Z6 shall not exceed 0.3%, the contents of LMS1-Z10, LMS1-Z11, LMS1-Z12 and LMS1-Z13 shall not exceed 0.15%, the content of unknown impurities shall not exceed 0.1%, and the total impurities shall not exceed 1.0%.

[0091] The following uses the method of comparative examples to detect various impurities in the starting material LMS1 of lumateperone.

[0092] Comparative Example 1. Detection method for various impurities in the starting material LMS1 of lumateperone

[0093] Adopt 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) to detect various impurities in the starting material LMS1 of the present invention of lumateperone.

[0094] (1) Instrument: Shimadzu 2030 liquid chromatograph;

[0095] (2) Chromatographic conditions:

[0096] Use 0.025 mol / L potassium dihydrogen phosphate solution (adjust the pH to 2.5 with phosphoric acid) as mobile phase A, and use methanol-acetonitrile (50:50) as mobile phase B, and perform gradient elution according to the following table:

[0097]

[0098] Chromatographic column: YMC-Pack Pro C18, 4.6 mm×150 mm, 3 μm;

[0099] Detector: UV detector, detection wavelength 254 nm;

[0100] Column temperature: 20 °C;

[0101] Flow rate: 1.0 ml / min;

[0102] Injection volume: 10 μl;

[0103] (3) Preparation of solutions:

[0104] Diluent: Acetonitrile - water (50:50);

[0105] System suitability solution: Take impurity reference substances (LMS1 - Z4, LMS1 - Z6, LMS1 - Z10, LMS1 - Z11, LMS1 - Z12, LMS1 - Z13) and the reference substance of the main component LMS1 respectively, 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.

[0106] LMS1 - Z10 localization solution: Weigh accurately 5.087 mg of the impurity LMS1 - Z10 reference substance, place it in a 10 - ml volumetric flask, dissolve with the diluent and dilute to the mark, shake well. Pipette 50 μl of this solution, dissolve with the diluent and dilute to 5 ml, shake well to obtain the solution.

[0107] (4) Detection:

[0108] Precisely pipette 10 μl each of the system suitability solution and the LMS1 - Z10 localization solution, inject them into the liquid chromatograph, and record the chromatogram.

[0109] (5) Experimental results:

[0110] 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.

[0111] Comparative Example 2. Detection method for multiple impurities in the starting material LMS1 of lumateperone

[0112] (1) Instrument: Shimadzu 2030 liquid chromatograph;

[0113] (2) Chromatographic conditions:

[0114] 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:

[0115]

[0116] Chromatographic column: ODS - SP C18, 250 mm × 4.6 mm, 5 μm;

[0117] Detector: UV detector, detection wavelength 210 nm;

[0118] Column temperature: 40°C;

[0119] Flow rate: 1.0 ml / min;

[0120] Injection volume: 10 μl;

[0121] (3) Preparation of system suitability solution:

[0122] Respectively take impurity reference substances (LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13) and the reference substance of the main component LMS1, dissolve them with acetonitrile-water (50:50) and quantitatively dilute to prepare a solution containing 5 μg of each impurity and about 0.5 mg of LMS1 per 1 ml.

[0123] (4) Detection:

[0124] Precisely measure 10 μl of the system suitability solution, inject it into the liquid chromatograph, and record the chromatogram.

[0125] (5) Experimental results:

[0126] The experimental results ( Figure 5 ) show that the peaks of each impurity are relatively concentrated and relatively delayed, the responses of each impurity are low, and the method is not applicable.

[0127] The following conducts the methodological verification of the present invention through experimental examples.

[0128] Experimental Example 1. Methodological Verification

[0129] (1) Specificity

[0130] 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, inject them into the liquid chromatograph for detection. The liquid chromatogram is as Figures 1 - 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.

[0131] (2) Quantitation limit and detection limit

[0132] Stock solution of impurity LMS1-Z4 reference substance (1.5 mg / ml): Precisely weigh 15.181 mg of the impurity LMS1-Z4 reference substance, place it in a 10 ml volumetric flask, dissolve it with the diluent and dilute to the mark, and shake well.

[0133] Stock solution of LMS1-Z6 reference substance (1.5 mg / ml): Precisely weigh 15.461 mg of the LMS1-Z6 reference substance, place it in a 10 ml volumetric flask, dissolve it with the diluent and dilute to the mark, and shake well.

[0134] 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 it with diluent and dilute to the mark, then shake well.

[0135] 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 it with diluent and dilute to the mark, then shake well.

[0136] 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 it with diluent and dilute to the mark, then shake well.

[0137] 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 it with diluent and dilute to the mark, then shake well.

[0138] 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 it with diluent and dilute to the mark, then shake well.

[0139] Take each stock solution of the reference substance and dilute it step by step. Inject the samples for analysis according to the chromatographic conditions in Example 1, record the chromatograms. Take the signal-to-noise ratio of about 10 as the quantitative limit and the signal-to-noise ratio of about 3 as the detection limit. The detection limit and quantitative limit results of each component are shown in Table 2.

[0140] Table 2 Results of quantitative limits

[0141]

[0142] The experimental results show that the ratio of the concentration of the quantitative limit solution to the limit concentration of each impurity to be measured 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 to the limit concentration of each impurity to be measured is not greater than 3.0%, and the signal-to-noise ratio is not less than 3.01. The sensitivity meets the requirements.

[0143] (3) Linearity and range

[0144] Take appropriate amounts of the stock solutions of LMS1-Z4, LMS1-Z6, LMS1-Z10, LMS1-Z11, LMS1-Z12, LMS1-Z13 and LMS1 reference substances under the sensitivity item, dilute them with methanol to prepare a series of linear solutions. Inject the samples for analysis according to the chromatographic conditions in Example 1, record the chromatograms. 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.

[0145] Table 3 Linear Relationship Results Table

[0146]

[0147] The results show that there is a good linear relationship between the main component and each impurity within the linear range of the quantitative limit to 200% limit.

[0148] (4) Repeatability

[0149] Solvent: Acetonitrile - water (50:50).

[0150] Reference solution: Take the reference substance of lumateperone starting material LMS1, weigh accurately, dissolve with the solvent and quantitatively dilute to prepare a solution containing about 1.5 μg per 1 ml.

[0151] Test solution: Take the test substance of LMS1, weigh accurately, dissolve with the solvent and quantitatively dilute to prepare a solution containing about 0.5 mg per 1 ml, and prepare 6 parallel portions.

[0152] 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 with the peak area, and the results are shown in Table 4.

[0153] Table 4 Repeatability Results Table

[0154]

[0155] The experimental results show that for 6 parallel test solutions of the test substance, when calculating the content of each impurity by the external standard method of the main component with the correction factor, the detected amounts of each impurity to be measured all meet the standards described in Example 1, and the RSD of the detected amounts of each impurity to be measured are all not more than 4.4%, and the repeatability meets the requirements.

[0156] (5) Accuracy

[0157] Diluent: Acetonitrile - water (50:50).

[0158] Test solution (base value): Refer to the data of "Repeatability".

[0159] Take 3 portions each of the standard stock solutions under the sensitivity item to prepare 20%, 100%, and 150% spiked recovery solutions, inject and analyze according to the chromatographic conditions in Example 1, record the chromatogram, and calculate the recovery rate of the impurity to be measured in each recovery solution by the external standard method of the impurity; the results are shown in Table 5.

[0160] Table 5 Accuracy Results Table

[0161]

[0162] The experimental results show that for each impurity to be tested within the limit concentration range of 20% - 150%, the recovery rates of each impurity are between 91.59% and 108.94%, and the RSDs are not greater than 4.2%, meeting the requirements for accuracy.

[0163] (6) Solution stability

[0164] Take the reference solution and the test solution, place them at room temperature, inject samples for analysis at different time intervals, record the chromatograms, and statistically analyze the relative standard deviations of the peak areas or contents of each impurity in each solution. The test results are shown in Table 6.

[0165] Table 6 Results of solution stability

[0166]

[0167] The experimental results show that the reference solution and the test solution are stable within 6 days at room temperature.

[0168] (7) Robustness

[0169] Diluent, system suitability solution, reference solution, and test solution: the same as those under "Repeatability".

[0170] Fine-tune the chromatographic method parameters according to Table 7, inject the above solutions for analysis respectively, record the chromatograms, and calculate the contents of each impurity by the external standard method with the main component. The results are shown in Table 8.

[0171] Table 7 Chromatographic parameters for robustness

[0172]

[0173] Table 8 Summary of robustness results

[0174]

[0175] 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 tested, the resolution between impurity peaks in the system suitability solution is not less than 1.2, 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 tested in the test solution meet the requirements, and the RSDs are not greater than 8.9%. The method robustness meets the requirements.

[0176] In summary, the method for determining the impurities in the starting material LMS1 of lumateperone in the present invention has strong specificity, high sensitivity, and good linearity, repeatability, accuracy, solution stability, and robustness.

[0177] In summary, the present invention provides a method for detecting impurities in lumateperone starting material LMS1. This method can simultaneously and accurately quantify three isomers and three process impurities in lumateperone starting material LMS1, 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.

[0178] Obviously, the above description is only a preferred embodiment of the present invention, merely an example clearly illustrating the present invention, rather than a limitation on the embodiments of the present invention. It should be noted that for those of ordinary skill in the art in this technical field, 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 enumerate all the embodiments here. Any modifications, equivalent improvements, substitutions, etc. made within the spirit and principle of the present invention shall be included within 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 impurity reference substance 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 chemically bonded 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.

2. The method according to claim 1, wherein 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, wherein 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, wherein 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 impurity reference substance 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 impurities 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 - 9. The method according to claim 1, characterized in that, ​ 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. The method according to 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.

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