A new crystalline form of valbenazine di-p-toluenesulfonate and methods of making and using the same

Abstract

This invention provides a novel crystalline form of valbenazine di-p-toluenesulfonate and its preparation method, as well as its use in the preparation of drugs for treating tardive dyskinesia. The novel crystalline form of valbenazine di-p-toluenesulfonate provided by this invention has significant advantages in terms of stability, hygroscopicity, flowability, raw material purification effect, and dissolution rate. The preparation method of the novel crystalline form has a high product yield, is simple to operate, requires less time, and has low energy consumption, making it more suitable for industrial applications.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a new crystal form of valbenazine di-toluenesulfonate, its preparation method, and its uses. Background Technology

[0002] Valbenazine, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,la]isoquinoline-2-yl ester, is a prodrug of the purified (+)-α-isomer of dihydrobenazine, and has shown unique therapeutic effects on hypermotor dyskinesia (including tardive dyskinesia symptoms).

[0003] Valbenazine, developed by Neurocrine Biosciences, is used to treat adult patients with tardive dyskinesia. It is marketed in the form of di-toluenesulfonate and was approved by the FDA in April 2017 for the treatment of tardive dyskinesia.

[0004] Drug polymorphism refers to the significant differences in appearance, melting point, density, hardness, solubility, dissolution rate, and bioavailability of different crystal forms of the same drug, thus affecting its stability, bioavailability, and other pharmaceutical properties. Therefore, polymorphism research is an important part of the drug development process and an indispensable part of drug quality control. Currently, there are numerous reports on the crystal forms of valbenazine di-toluenesulfonate.

[0005] Patent CN108473489B discloses six crystal forms of vabenazine di-p-toluenesulfonate, namely crystal form I, crystal form II, crystal form III, crystal form IV, crystal form V and crystal form VI. The patent specification details the stability data of crystal form I and clearly points out that the stability of form I is far superior to that of form II and form IV, which is the optimal crystal form disclosed in the patent.

[0006] Patent CN110621674B discloses crystal form A of valbenazine di-p-toluenesulfonate and describes the preparation method, stability, hygroscopicity, and other data of crystal form A.

[0007] The inventors of this application have discovered that, according to the method in Example 2 of patent CN108473489B, the yield of crystalline form I is only 69% for the crude product and only 50%–61% for the refined product, resulting in significant raw material loss and high costs. The method in Example 3 of patent CN110621674B, which yields 84% ​​for crystalline form A, is an improvement over patent CN108473489B, but still not ideal. Furthermore, it requires transformation through an intermediate crystalline form, which is time-consuming and energy-intensive, hindering industrial production. Moreover, research has shown that crystalline form I and crystalline form A have certain problems in terms of stability, hygroscopicity, and powder properties.

[0008] To overcome the shortcomings of the prior art, the inventors of this application have discovered a new crystal form of valbenazine di-toluenesulfonate, named "Crystal Form B". This crystal form has significant advantages in terms of stability, hygroscopicity, flowability, raw material purification effect, and dissolution, providing a better option for the drug development of valbenazine di-toluenesulfonate. Summary of the Invention

[0009] The main objective of this invention is to provide a crystal form B of valbenazine di-p-toluenesulfonate, its preparation method, and its uses. The structure of valbenazine di-p-toluenesulfonate is shown in formula (I) below:

[0010]

[0011] In one aspect, the present invention provides a crystalline form B of valbenazine di-p-toluenesulfonate, wherein, using Cu-Kα radiation, the X-ray powder diffraction pattern of crystalline form B exhibits diffraction peaks at 2θ values ​​of 6.8°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.3°±0.2°, 15.8°±0.2°, and 18.6°±0.2°.

[0012] Furthermore, the X-ray powder diffraction pattern of crystal form B exhibits diffraction peaks at 2θ values ​​of 5.8°±0.2°, 6.8°±0.2°, 7.6°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.3°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 16.9°±0.2°, 18.6°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.8°±0.2°, 22.4°±0.2°, and 26.5°±0.2°.

[0013] Non-limiting, in one specific embodiment of the invention, crystal form B is a monohydrate, and its X-ray powder diffraction pattern is as follows: Figure 1 As shown.

[0014] The FT-IR spectrum of crystal form B of the present invention is at 419.379 cm⁻¹. -1 (w), 565.519cm -1 (w), 683.467cm -1 (w), 814.845cm -1 (w), 863.416cm -1 (w), 941.100cm -1 (w), 1011.687cm -1 (w), 1038.709cm -1 (w), 1124.044cm -1 (w), 1210.493cm -1 (w), 1268.583cm -1 (w), 1376.944cm -1 (w), 1389.296cm -1 (w), 1466.998cm -1 (w), 1522.989cm -1 (w), 1631.547cm -1 (w), 1744.940cm -1 (w), 2632.443cm -1 (w), 2960.560cm -1 (w) and 3415.915cm -1 There is an absorption peak at (w).

[0015] Another aspect of the present invention provides a method for preparing crystalline form B of valbenazine di-p-toluenesulfonate, characterized by comprising: dissolving a compound of formula (II) in dichloromethane, then adding anhydrous p-toluenesulfonic acid, controlling the temperature of the reaction system at 30±5℃, stirring while maintaining the temperature, filtering the solid, and drying to obtain crystalline form B, the structure of the compound of formula (II) is shown below:

[0016]

[0017] In one embodiment, in the method for preparing crystal form B, after dissolving the compound of formula (II) in dichloromethane, an appropriate amount of purified water is added to the reaction system.

[0018] In one embodiment, the molar ratio of the purified water to the compound of formula (II) is 1 to 5:1.

[0019] In one embodiment, the molar ratio of the compound of formula (II) to anhydrous p-toluenesulfonic acid is 1:1.9 to 2.2.

[0020] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of crystal form B of the present invention and a pharmaceutically acceptable carrier or excipient.

[0021] Furthermore, the use of crystal form B provided by the present invention in the preparation of drugs for treating tardive dyskinesia.

[0022] The beneficial effects of this invention are reflected in:

[0023] 1. Compared with the existing crystal forms I, II, and A, the crystal form B of this invention has significant advantages in terms of stability, hygroscopicity, fluidity, raw material purification effect, and dissolution.

[0024] 2. The method for preparing crystal form B in this invention has a high product yield, is simple to operate, takes less time, and has low energy consumption, making it more suitable for industrial applications. Attached Figure Description

[0025] Figure 1 This is an exemplary XRPD diagram of valbenazine di-toluenesulfonate crystal form B.

[0026] Figure 2 This is an exemplary TGA diagram of valbenazine di-p-toluenesulfonate crystal form B.

[0027] Figure 3 This is an exemplary DSC diagram of valbenazine di-p-toluenesulfonate crystal form B.

[0028] Figure 4 This is an exemplary FT-IR spectrum of valbenazine di-toluenesulfonate crystal form B.

[0029] Figure 5 This is a comparison of XRPD before and after the stability test of valbenazine di-toluenesulfonate crystal form B in Example 5.

[0030] Figure 6 This is a comparison of XRPD before and after grinding of valbenazine di-toluenesulfonate crystal form B in Example 6. Detailed Implementation

[0031] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention.

[0032] In this invention, numerical ranges are involved. Unless otherwise specified, the numerical ranges are considered continuous and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0033] The embodiments of this application will be described in detail below with reference to examples. Unless otherwise specified, the raw materials used in the following examples are all commercially available products.

[0034] The abbreviations used in this invention are explained as follows:

[0035] XRPD: X-ray powder diffraction

[0036] DSC: Differential Scan Calorimetry

[0037] TGA: Thermogravimetric Analysis

[0038] FT-IR: Fourier Transform Infrared Spectroscopy

[0039] Instruments and methods used for data collection:

[0040] The X-ray powder diffraction data and XRPD patterns described in this embodiment of the invention were acquired on a Bruker D2 Phaser X-ray powder diffractometer. The test conditions were: current intensity 10mA, voltage 30kV, step size 0.043°, Cu target, scanning range 3° to 40°, and scanning time 150 seconds.

[0041] The DSC chart described in this embodiment of the invention was acquired on a TA Instruments DSC55 differential scanning calorimeter. The test conditions were: temperature range of 20 to 300°C, heating rate of 10°C / minute, and purging with nitrogen.

[0042] The TGA chart described in this embodiment of the invention was acquired on a TA Instruments TGA25 thermogravimetric analyzer. The test conditions were: temperature range of room temperature to 300°C, heating rate of 10°C / min, and purging with nitrogen.

[0043] The FT-IR images described in this embodiment of the invention were acquired on a Thermo Fourier Transform Infrared Spectrometer, and the testing method was the KBr pellet method.

[0044] Example 1: Preparation of Valbenazine di-p-toluenesulfonate crystal form B

[0045] 492 mL of a dichloromethane solution of compound (II) (containing 45.7 mg / mL of compound (II)) was added to a double-glass jacketed reactor. 100 mL of dichloromethane was added and the mixture was evaporated at 40°C until an oily substance was obtained. 450 mL of dichloromethane was added, and the system was cooled to 30°C. 0.97 g of purified water was then added to the reactor. 18.52 g of anhydrous p-toluenesulfonic acid was added in portions, and the mixture was stirred at 30°C for 2 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 45°C to obtain 39.93 g of solid, with a yield of 95.1% and a purity of 99.90%. The solid was identified as vabenazine di-p-toluenesulfonate crystal form B. The X-ray powder diffraction data for crystal form B are shown in Table 1, and its XRPD pattern is shown in Figure 1. Figure 1 As shown. The TGA image of crystal form B is as follows. Figure 2 As shown, the DSC diagram is as follows Figure 3 As shown, the FT-IR plot is as follows Figure 4 As shown.

[0046] Table 1

[0047]

[0048]

[0049] Figure 2 The TGA image of crystal form B is shown. Crystal form B exhibits approximately 2.3% mass loss upon heating to 150.0℃ (instrument error ±0.2%). Heating the crystal form B sample to 170℃ causes it to transform into an amorphous form. The water content of the crystal form B sample, determined by Karl Fischer titration, is 2.35%. The theoretical weight loss of vabenazine di-toluenesulfonate monohydrate is 2.31%. Combining the TGA test results and the heating experiment results, crystal form B is confirmed to be a monohydrate.

[0050] Figure 3 The DSC diagram of crystal form B is shown. Crystal form B exhibits endothermic peaks when heated to 141.4℃ (initial temperature) and 156.0℃ (peak temperature).

[0051] Figure 4 The FT-IR spectrum of crystal form B is shown. Crystal form B is located at 419.379 cm⁻¹. -1 (w), 565.519cm -1 (w), 683.467cm -1 (w), 814.845cm -1 (w), 863.416cm -1 (w), 941.100cm -1 (w), 1011.687cm -1 (w), 1038.709cm -1 (w), 1124.044cm -1(w), 1210.493cm -1 (w), 1268.583cm -1 (w), 1376.944cm -1 (w), 1389.296cm -1 (w), 1466.998cm -1 (w), 1522.989cm -1 (w), 1631.547cm -1 (w), 1744.940cm -1 (w), 2632.443cm -1 (w), 2960.560cm -1 (w) and 3415.915cm -1 There is an absorption peak at (w).

[0052] Example 2 Preparation of valbenazine di-p-toluenesulfonate crystal form B

[0053] 137 mL of a dichloromethane solution of compound (II) (containing 40.1 mg / mL of compound (II)) was placed in a double-glass jacketed reactor. 100 mL of dichloromethane was added, and the mixture was evaporated at 40°C until an oily substance was obtained. 200 mL of dichloromethane was added, and the system was cooled to 30°C. 0.24 g of purified water was then added to the reactor. 4.2 g of anhydrous p-toluenesulfonic acid was added in portions, and the mixture was stirred at 30°C for 2 hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 45°C to obtain 9.47 g of solid, with a yield of 94.7% and a purity of 99.91%. The obtained solid was identified as vabenazine di-p-toluenesulfonate crystal form B.

[0054] Example 3 investigated the effect of water volume on the preparation results of valbenazine di-p-toluenesulfonate crystal form B.

[0055] 5.0 g of compound (II) was weighed into a 250 mL double-glass jacketed reactor, 100.0 mL of dichloromethane and different equivalents of purified water were added, followed by 4.5 g of anhydrous p-toluenesulfonic acid. The reaction system was heated to 30℃±5℃ and stirred for several hours. The mixture was filtered, and the filter cake was dried under reduced pressure at 45℃. The solid was then subjected to qualitative and quantitative analysis. Under the same conditions, only the molar ratio of water to compound (II) was changed to conduct a single-factor experiment. The experimental results are shown in Table 2.

[0056] Table 2

[0057]

[0058] As can be seen from the data in Table 2, when no water is added to the reaction system, the purity of the crystal form B obtained from the reaction is high, but the reaction yield is low; when the molar ratio of water to compound (II) in the reaction system is 1 to 5, both the reaction yield and the purity of the obtained crystal form B are high.

[0059] Example 4: Stability Study of Valbenazine Di-p-Toluenesulfonate Crystal Form B

[0060] A certain amount of valbenazine di-toluenesulfonate crystal form B prepared in Example 1 was placed in an open container at 5°C, 60°C, 75% RH, and under light for a period of time. Samples were taken and analyzed before and after this period. The crystal form was determined by XRPD, and the purity was determined by HPLC. The results are shown in Table 3. Figure 5 As shown.

[0061] Table 3

[0062]

[0063] The HPLC results in Table 3 show that the main purity of crystal form B did not change significantly after being left exposed for 30 days under conditions of 5℃, 60℃, 75%RH and light irradiation.

[0064] Figure 5 The XRPD results showed that crystal form B was stable for at least 30 days under conditions of 5℃, 60℃, 75%RH, and light irradiation.

[0065] Example 5: Study on the mechanical stability of valbenazine di-p-toluenesulfonate crystal form B

[0066] Weigh 0.2g of valbenazine di-p-toluenesulfonate crystal form B prepared in Example 1 into an agate mortar and grind clockwise for 5 minutes. XRPD tests were performed on the samples before and after grinding. The results are shown in [Figure 1]. Figure 6 As shown.

[0067] The results showed that the crystal form of valbenazine di-toluenesulfonate B remained unchanged after grinding, and it exhibited good mechanical stability.

[0068] Example 6: Comparative Study of Preparation Methods of Different Valbenazine Di-p-Toluenesulfonate Crystal Forms

[0069] The products were prepared according to the preparation methods of crystal form B, crystal form I (CN108473489B), and crystal form A (CN110621674B) of this patent, respectively. The preparation process and product quality were compared, and the comparison results are shown in Table 4 below.

[0070] Table 4

[0071]

[0072]

[0073] As shown in the table above, the preparation method for crystal form I has a low yield and requires a cyclic heating and cooling process, making the unit operation steps complex, with long ripening and drying times, resulting in poor economic efficiency. The preparation method for crystal form A requires the intermediate crystal form CSIII, which involves complex steps, long operation time, and high energy consumption. In this invention, crystal form B is obtained by direct salt formation of compound (II) and anhydrous p-toluenesulfonic acid in dichloromethane and purified water. The preparation process is simple, the entire reaction is carried out at 30°C, the crystallization time is short, the energy consumption is low, and the product yield is high.

[0074] Example 7: Study on the purification effect of valbenazine di-p-toluenesulfonate crystal form B

[0075] Crystal form B was prepared according to the method in Example 1. Crystal forms I, II and A were prepared according to existing methods. The purity of the starting material, crystal form B, crystal form I, II and A was determined by HPLC. The test results are shown in Table 5.

[0076] Table 5

[0077] sample purity(%) Number of impurities Maximum single impurity (%) Purity increase (%) Starting materials 99.20 18 0.38 / Crystal form B 99.90 7 0.04 0.70 Crystal form I 99.65 11 0.14 0.45 Crystal form II 99.57 12 0.17 0.37 Crystal form A 99.66 11 0.13 0.46

[0078] As shown in Table 5, the purity of crystal form B was significantly improved after preparation from the starting material, increasing from 99.20% to 99.90%. The number of impurities decreased from 18 to 7, and the maximum single impurity content decreased from 0.38% to 0.04%. This indicates that crystal form B has a better purification effect compared with crystal form I, crystal form II and crystal form A in the existing technology.

[0079] Example 8: Flowability study of valbenazine di-p-toluenesulfonate crystal form B

[0080] Powder flowability is closely related to the pharmaceutical manufacturing process and the quality of the finished product, and therefore has wide applications in drug research. Compressibility and the closely related Hausner ratio are simple methods for predicting powder flowability, and the correspondence between compressibility, Hausner ratio and flowability evaluation is shown in Table 6 below.

[0081] Table 6

[0082] Hausner Liquidity Compression (%) 1.00-1.11 very good ≤10 1.12-1.18 good 11～15 1.19-1.25 better 16～20 1.26-1.34 acceptable 21～25 1.35-1.45 Difference 26～31 1.46-1.59 Very bad 32～37 >1.60 Range ＞38

[0083] A certain amount of samples of crystal form B of this invention and crystal forms I and II of the prior art were taken for Hausner ratio testing. The test method was as follows: A tapper was used in this experiment, and the fixed volume method was followed. Specifically, the weighed powder was placed into a 10mL graduated cylinder, which was then fixed to a support. The cylinder was vibrated at 55±5 times per minute for 6-8 minutes. The volume change of the powder in the graduated cylinder was measured. The ratio of the powder mass to the volume of the material before tapping is the loose density of the powder, and the ratio of the powder mass to the volume of the material after tapping is the tapped density of the powder. Hausner ratio = tapped density / loose density; compressibility = (tapped density - loose density) / tapped density. The test and calculation results are shown in Table 7.

[0084] Table 7

[0085] sample <![CDATA[Bulk density (g / cm 3 )]]> <![CDATA[Tap density (g / cm 3 )]]> Hausner ratio Compression (%) Crystal form B 0.217 0.269 1.24 19 Crystal form I 0.217 0.294 1.35 26 Crystal form II 0.220 0.283 1.29 22

[0086] Experimental results show that crystal form B of this patent has better fluidity, while crystal form I in the prior art has poor fluidity, and crystal form II in the prior art has acceptable fluidity. The fluidity of crystal form B of this invention is superior to that of crystal forms I and II in the prior art.

[0087] Example 9: Hygroscopicity Study of Valbenazine Di-p-Toluenesulfonate Crystal Form B

[0088] The hygroscopicity test was conducted according to the guidelines for hygroscopicity testing of drugs in General Chapter 9103 of the 2020 edition of the Chinese Pharmacopoeia. The experimental method is as follows:

[0089] 1. Take a dry, stoppered glass weighing bottle (outer diameter 50 mm, height 15 mm), place it in a suitable constant temperature desiccator at 25±1℃ one day before the test (with a saturated solution of ammonium chloride or ammonium sulfate placed at the bottom), and accurately weigh it as m1.

[0090] 2. Take an appropriate amount of the test sample and spread it evenly in the weighing bottle mentioned above. The thickness of the test sample is generally about 1 mm. Accurately weigh the sample m2.

[0091] 3. Leave the weighing bottle open and place it, along with the cap, under the above-mentioned constant temperature and humidity conditions for 24 hours.

[0092] 4. Close the weighing bottle cap and accurately weigh the contents (m3).

[0093] Calculation formula: Percentage weight gain = (m3-m2) / (m2-m1)*100%.

[0094] The hygroscopicity data of crystal form B of the present invention were tested, and the corresponding weight gain percentage was calculated. The hygroscopicity results of crystal form A, crystal form I and crystal form II disclosed in the prior art (patents CN110621674B, CN108473489B) were compared, and the results are shown in Table 8.

[0095] Table 8

[0096]

[0097] The results showed that the hygroscopic weight gain percentage of crystal form B was only 0.011%, while the hygroscopic weight gain percentages of crystal form I, crystal form II, and crystal form A disclosed in the prior art were 0.4%, 0.32%, and 0.24%, respectively. Therefore, the hygroscopicity of crystal form B in this invention is significantly superior to that of crystal forms I, II, and A. Example 10: Preparation of formulation of valbenazine di-p-toluenesulfonate crystal form B.

[0098] According to the formulation formula in Table 9, valbenazine di-toluenesulfonate crystal form B was prepared as follows: Each component was weighed into an LDPE bag according to the formula and manually mixed for 2 minutes; tablets were compressed using a single-punch manual tablet press (mold: φ20mm round; tablet weight: 500mg; pressure: 5±0.5KN); the lumps were crushed using a mortar and pestle and passed through a 20-mesh sieve; magnesium stearate, an added excipient, was weighed and mixed with the granules obtained by the above dry granulation method, placed in an LDPE bag, and manually mixed for 2 minutes; 200mg±2mg of the total mixture was weighed and filled into #1 capsule shells; bottling: one capsule per 35cc HDPE bottle with 1g of desiccant added.

[0099] Table 9

[0100] Element mg / particle Crystal form B 73.0 Mannitol (160°C) 106.0 Partially pregelatinized starch (Starch 1500) 18.0 Colloidal silica (AEROSIL 200Pharma) 1.0 Magnesium stearate (5712), added in two portions. 2.0 total 200

[0101] During the preparation of the formulation from crystal form B, XRPD analysis showed that the crystal form of the active pharmaceutical ingredient remained unchanged after granulation, indicating that crystal form B remained stable during the granulation process.

[0102] Example 11: In vitro dissolution study of valbenazine di-p-toluenesulfonate crystal form B.

[0103] The capsules containing crystalline form B obtained in Example 10 were subjected to in vitro dissolution testing under the following conditions:

[0104] Dissolution medium: 0.1 mol / L HCl solution

[0105] Dissolution method: Paddle method + settling basket

[0106] Media volume: 900mL

[0107] Speed: 50 rpm

[0108] Medium temperature: 37℃

[0109] The test results are shown in Table 10 below.

[0110] Table 10

[0111] Time (min) Cumulative dissolution rate / % 0 0.0 5 20.5 10 50.5 15 68.9 20 77.5 30 90.4

[0112] The results showed that the capsules containing valbenazine di-p-toluenesulfonate crystal form B as the active ingredient achieved a dissolution rate of over 90% within 30 minutes, meeting the requirements for rapid dissolution and demonstrating good dissolution performance.

[0113] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0114] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A crystalline form B of valbenazine di-p-toluenesulfonate, characterized in that, Its X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 6.8°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.3°±0.2°, 15.8°±0.2°, and 18.6°±0.2°. The structure of valbenazine di-toluenesulfonate is shown in formula (I) below:

2. The crystal form B according to claim 1, characterized in that, Its X-ray powder diffraction pattern shows diffraction peaks at 2θ values ​​of 5.8°±0.2°, 6.8°±0.2°, 7.6°±0.2°, 10.1°±0.2°, 13.7°±0.2°, 14.3°±0.2°, 15.3°±0.2°, 15.8°±0.2°, 16.9°±0.2°, 18.6°±0.2°, 19.8°±0.2°, 20.2°±0.2°, 20.8°±0.2°, 22.4°±0.2°, and 26.5°±0.2°.

3. Crystal form B according to claim 1 or 2, characterized in that, Its X-ray powder diffraction pattern is shown in Figure 1.

4. A method for preparing crystal form B as described in any one of claims 1 to 3, characterized in that, include: Compound (II) was dissolved in dichloromethane, and then anhydrous p-toluenesulfonic acid was added. The reaction system temperature was controlled at 30±5℃, and the mixture was stirred while maintaining the temperature. The solid was filtered and dried to obtain crystal form B. The structure of compound (II) is shown below:

5. The preparation method according to claim 4, characterized in that, include: After dissolving the compound of formula (II) in dichloromethane, an appropriate amount of purified water is added to the reaction system.

6. The preparation method according to claim 5, characterized in that, The molar ratio of purified water to compound of formula (II) is 1 to 5:

1.

7. The preparation method according to claim 4, characterized in that, The molar ratio of the compound of formula (II) to anhydrous p-toluenesulfonic acid is 1:1.9 to 2.

2.

8. A pharmaceutical composition comprising crystal form B as described in any one of claims 1 to 3 and a pharmaceutically acceptable carrier or excipient.

9. Use of crystal form B according to any one of claims 1 to 3 in the preparation of a medicament for treating tardive dyskinesia.

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