Crystalline forms of ozanimod and ozanimod hydrochloride, and processes for preparation thereof

Abstract

The present disclosure is directed to novel crystalline forms of ozanimod and ozanimod hydrochloride, as well as preparation method thereof. Said crystalline forms of ozanimod and ozanimod hydrochloride can be used for treating autoimmune diseases, particularly used for preparing drugs for treating multiple sclerosis and ulcerative colitis. The crystalline forms of the present disclosure have one or more advantages in solubility, melting point, stability, dissolution, bioavailability and processability and provide new and better choices for the preparation of ozanimod drug product, and are very valuable for drug development. ##STR00001##

Claims

1. A crystalline Form CS1 of ozanimod hydrochloride, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 26.1°±0.20°, 24.4°±0.20° and 20.1°±0.20° using CuKα radiation.

2. The crystalline Form CS1 of ozanimod hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 3.9°±0.20°, 21.1°±0.20° and 7.9°±0.20° using CuKα radiation.

3. The crystalline Form CS1 of ozanimod hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 11.9°±0.20°, 19.6°±0.20° and 13.8°±0.20° using CuKα radiation.

4. A process for preparing crystalline Form CS1 of ozanimod hydrochloride according to claim 1, wherein the process comprises method 1) or method 2) or method 3) or method 4) or method 5), 1) adding ozanimod hydrochloride into an ether and stirring at 4-50° C., filtering and drying to obtain a white solid of Form CS1 of ozanimod hydrochloride; said stirring time is at least 0.5 hour; or 2) dissolving ozanimod hydrochloride into a mixture of an alcohol and an ester, evaporating at room temperature to obtain a white solid of Form CS1 of ozanimod hydrochloride; said evaporating time is at least 0.5 day; or 3) dissolving ozanimod hydrochloride into a solvent selected from an amide or a mixture of solvents thereof, then placing the solution in a system containing an antisolvent of ozanimod hydrochloride for liquid vapor diffusion at room temperature, filtering and drying to obtain a white solid of Form CS1 of ozanimod hydrochloride; said diffusion time is at least 1 day; or 4) dissolving ozanimod hydrochloride into a mixture of an alcohol and water to form a supersaturated solution, ozanimod hydrochloride is fully dissolved at 25-80° C. and then filtering, cooling the filtrate for precipitation, filtering and drying to obtain a white solid of Form CS1 of ozanimod hydrochloride; or 5) dissolving ozanimod hydrochloride into an alcohol in a concentration of 12 mg/mL to form an alcohol solution, filtering and evaporating the alcohol solution at room temperature for 1 week to obtain a white solid of Form CS1 of ozanimod hydrochloride.

5. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline Form CS1 of ozanimod hydrochloride according to claim 1 and a pharmaceutically acceptable carrier, a diluent or an excipient.

6. A method of treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline Form CS1 of ozanimod hydrochloride according to claim 1.

7. A method of treating multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of crystalline Form CS1 of ozanimod hydrochloride according to claim 1.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows an XRPD pattern of Form CS1 obtained in Example 1.

(2) FIG. 2 shows a DSC curve of Form CS1 obtained in Example 1.

(3) FIG. 3 shows a TGA curve of Form CS1 obtained in Example 1.

(4) FIG. 4 shows an XRPD pattern of Form CS2 obtained in Example 3.

(5) FIG. 5 shows a DSC curve of Form CS2 obtained in Example 3.

(6) FIG. 6 shows a TGA curve of Form CS2 obtained in Example 3.

(7) FIG. 7 shows an XRPD pattern of Form CS3 obtained in Example 5.

(8) FIG. 8 shows a DSC curve of Form CS3 obtained in Example 5.

(9) FIG. 9 shows a TGA curve of Form CS3 obtained in Example 5.

(10) FIG. 10 shows an XRPD pattern of Form CS5 obtained in Example 8.

(11) FIG. 11 shows a DSC curve of Form CS5 obtained in Example 8.

(12) FIG. 12 shows an XRPD pattern of Form CS6 obtained in Example 9.

(13) FIG. 13 shows a DSC curve of Form CS6 obtained in Example 10.

(14) FIG. 14 shows a TGA curve of Form CS6 obtained in Example 10.

(15) FIG. 15 shows an XRPD pattern of Form CS3 obtained in Example 6.

(16) FIG. 16 shows an XRPD pattern of Form CS6 obtained in Example 10.

(17) FIG. 17 shows an XRPD pattern of Form CS1 of hydrochloride.

(18) FIG. 18 shows a DSC curve of Form CS1 of hydrochloride obtained in Example 11.

(19) FIG. 19 shows a TGA curve of Form CS1 of hydrochloride obtained in Example 11.

(20) FIG. 20 shows an XRPD pattern of Form CS1 of hydrochloride obtained in Example 11.

(21) FIG. 21 shows an XRPD pattern of Form CS1 of hydrochloride obtained in Example 12.

(22) FIG. 22 shows an XRPD pattern of Form CS1 of hydrochloride obtained in Example 13.

(23) FIG. 23 shows an XRPD pattern of Form CS1 of hydrochloride obtained in Example 14.

(24) FIG. 24 shows an XRPD pattern of Form CS1 of hydrochloride obtained in Example 15.

(25) FIG. 25 shows a DVS plot of Form CS1 in Example 16.

(26) FIG. 26 shows a DVS plot of Form CS2 in Example 17.

(27) FIG. 27 shows a DVS plot of Form CS3 in Example 18.

(28) FIG. 28 shows a DVS plot of Form CS5 in Example 19.

(29) FIG. 29 shows a DVS plot of Form CS6 in Example 20.

(30) FIG. 30 shows a DVS plot of Form CS1 of hydrochloride in Example 21.

(31) FIG. 31 shows an XRPD comparison pattern of Form CS1 before and after stability test in Example 22.

(32) FIG. 32 shows an XRPD comparison pattern of Form CS2 before and after stability test in Example 23.

(33) FIG. 33 shows an XRPD comparison pattern of Form CS3 before and after stability test in Example 24.

(34) FIG. 34 shows an XRPD comparison pattern of Form CS5 before and after stability test in Example 25.

(35) FIG. 35 shows an XRPD comparison pattern of Form CS6 before and after stability test in Example 26.

(36) FIG. 36 shows an XRPD comparison pattern of Form CS1 of hydrochloride before and after stability test in Example 27.

(37) FIG. 37 shows a PSD diagram of Form CS1 in Example 28.

(38) FIG. 38 shows a PSD diagram of Form CS2 in Example 28.

(39) FIG. 39 shows a PSD diagram of Form CS3 in Example 28.

(40) FIG. 40 shows a PSD diagram of Form CS5 in Example 28.

(41) FIG. 41 shows a PSD diagram of Form CS6 in Example 28.

(42) FIG. 42 shows a PSD diagram of Form CS1 of hydrochloride in Example 28.

(43) FIG. 43 shows a PLM image of Form CS1 in Example 28.

(44) FIG. 44 shows a PLM image of Form CS2 in Example 28.

(45) FIG. 45 shows a PLM image of Form CS3 in Example 28.

(46) FIG. 46 shows a PLM image of Form CS5 in Example 28.

(47) FIG. 47 shows a PLM image of Form CS6 in Example 28.

(48) FIG. 48 shows a PLM image of Form CS1 of hydrochloride in Example 28.

(49) FIG. 49 shows an XRPD comparison pattern of Form CS3 before and after grinding test in Example 31.

(50) FIG. 50 shows an XRPD comparison pattern of Form CS5 before and after grinding test in Example 31.

(51) FIG. 51 shows an XRPD comparison pattern of Form CS6 before and after grinding test in Example 31.

(52) FIG. 52 shows an XRPD comparison pattern of Form CS1 of hydrochloride before and after grinding test in Example 31.

(53) FIG. 53 shows an XRPD pattern of Form CS3 in Example 7.

DETAILED DESCRIPTION OF THE DISCLOSURE

(54) The present disclosure is further illustrated by the following examples in detail, but is not intended to limit the scope of the present disclosure. The skilled in the art can make improvements to the process of preparation and the instruments used within the scope of the claims, and those improvements should be considered as falling into the scope of the present disclosure. Therefore, the protective scope of the present disclosure patent should be defined by the claims.

(55) In the following examples, the test method is generally implemented according to a conventional condition or a condition recommended by manufacturer.

(56) The abbreviations used in the disclosure are explained as follows:

(57) XRPD: X-ray Powder Diffraction

(58) DSC: Differential Scanning calorimetry

(59) TGA: Thermal Gravimetric Analysis

(60) DVS: Dynamic Vapor Sorption

(61) PSD: Particle Size Distribution

(62) PLM: Polarized Light microscopy

(63) X-ray powder diffraction pattern in the present disclosure was acquired by a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method of the present disclosure were as follows:

(64) X-ray Reflection: Cu, Kα

(65) Kα1 (Å): 1.540598; Kα2 (Å): 1.544426

(66) Kα2/Kα1 intensity ratio: 0.50

(67) Voltage: 45 (kV)

(68) Current: 40 (mA)

(69) Scan range: from 3.0 degree to 40.0 degree

(70) Differential scanning calorimetry (DSC) data in the present disclosure were acquired by a TA Q2000. The parameters of the differential scanning calorimetry (DSC) method of the present disclosure were as follow:

(71) Heating rate: 10° C./min

(72) Purge gas: nitrogen

(73) Thermal gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q5000. The parameters of the thermal gravimetric analysis (TGA) method of the present disclosure were as follow:

(74) Heating rate: 10° C./min

(75) Purge gas: nitrogen

(76) Dynamic Vapor Sorption (DVS) is measured via an SMS (Surface Measurement Systems Ltd.) intrinsic DVS. Typical Parameters for DVS test are as follows:

(77) Temperature: 25° C.

(78) Gas and flow rate: N.sub.2, 200 mL/min

(79) dm/dt: 0.002%/min

(80) RH range: 0% RH to 95% RH

(81) The particle size distribution test in the present disclosure is acquired by the S3500 laser particle size analyzer of Microtrac. Microtrac S3500 is equipped with the SDC (Sample Delivery Controller). The test is carried out by wet process, and the dispersion medium is Isopar G The parameters are as follow:

(82) TABLE-US-00001 Size distribution: Volume Run Time: 10 s Dispersion medium: Isopar G Particle coordinates: Standard Run Number: Average of 3 runs Fluid refractive index: 1.42 Particle Transparency:: Trans Residuals: Enabled Particle refractive index: 1.5 Flow rate: 60%* Particle shape: Irregular Filtration: Enabled Ultrasonication power: 30 W Ultrasonication time: 30 s *Flow rate 60% is 60% of 65 mL/s.

(83) Raw materials of ozanimod and/or a hydrochloride thereof used in the following examples are prepared by methods disclosed in CN102762100A.

Example 1

(84) Preparation of Form CS1 of Ozanimod:

(85) About 2.0 g of ozanimod hydrochloride was added into a 150-mL glass vial followed by adding 100 mL of methanol to form a suspension at room temperature. The suspension became clear after 7.0 mL of sodium hydroxide solution (32 mg/mL) was added dropwise. And then, white solid precipitated out after stirring at room temperature for 12 hours. The suspension was centrifuged and dried to isolate solid.

(86) The obtained solid was identified as Form CS1. The XRPD data of the solid prepared in this example are listed in Table 1. The XRPD pattern is displayed in FIG. 1. The DSC curve is displayed in FIG. 2. The TGA curve is displayed in FIG. 3.

(87) TABLE-US-00002 TABLE 1 Relative 2theta d spacing intensity % 4.24 20.83 53.60 7.37 12.00 20.87 8.78 10.07 3.91 10.45 8.46 60.36 12.07 7.33 100.00 12.82 6.90 9.66 14.19 6.24 6.17 16.17 5.48 1.63 17.19 5.16 4.96 17.65 5.02 9.86 18.22 4.87 7.35 18.69 4.75 1.61 20.18 4.40 2.40 21.51 4.13 9.64 21.95 4.05 2.44 22.35 3.98 5.65 22.82 3.90 3.25 23.51 3.78 2.32 24.35 3.66 19.15 24.74 3.60 3.72 25.69 3.47 0.86 26.63 3.35 0.75 27.30 3.27 1.49 28.60 3.12 1.52 30.90 2.89 2.80 31.26 2.86 1.01 32.44 2.76 0.57 33.63 2.67 1.87 34.77 2.58 0.91 36.41 2.47 1.13 39.25 2.30 1.49

(88) Use the preparation method of example 1, about 10 mg of ozanimod hydrochloride was suspended in methanol, acetone, isopropyl acetate or acetonitrile. The suspension became clear after 1.0-1.5 equivalent of sodium hydroxide solution was added. Then white solid precipitated out after stirring the solution at room temperature for 12 hours. The suspension was centrifuged to obtain solid. The solid was dried under vacuum. The obtained solid was identified as Form CS1 and its XRPD pattern was same as FIG. 1.

Example 2

(89) Preparation of Form CS1 of Ozanimod:

(90) About 10 mg of ozanimod and 0.5 mL of methanol was added into a 1.5-mL glass vial. The suspension was stirred at room temperature for 24 hours. The obtained white solid was identified as Form CS1 and its XRPD pattern was substantially the same as FIG. 1.

Example 3

(91) Preparation of Form CS2 of ozanimod:

(92) About 20 mg of Form CS1 of ozanimod was added into a 3-mL glass vial. And then, the solid was dried under vacuum at 110° C. for 1 hour. The obtained white solid was identified as Form CS2.

(93) The XRPD data of the solid prepared in this example are listed in Table 2. The XRPD pattern is displayed in FIG. 4. The DSC curve is displayed in FIG. 5. The TGA curve is displayed in FIG. 6.

(94) TABLE-US-00003 TABLE 2 Relative 2theta d spacing intensity % 3.96 22.33 20.48 7.95 11.12 11.39 12.02 7.36 4.10 13.33 6.64 35.96 14.16 6.25 21.29 15.89 5.58 19.75 17.72 5.00 12.52 18.49 4.80 36.64 20.08 4.42 11.25 20.77 4.28 4.59 21.36 4.16 7.46 21.53 4.13 8.77 22.56 3.94 8.50 23.19 3.84 100.00 24.22 3.67 4.08 24.97 3.57 3.68 26.47 3.37 17.30 27.46 3.25 3.66 28.40 3.14 1.16 29.98 2.98 28.43 31.45 2.84 1.01 32.19 2.78 2.21 34.53 2.60 0.69 37.45 2.40 0.61 38.43 2.34 0.73 39.50 2.28 1.41

Example 4A-4j

(95) Preparation of Form CS2 of Ozanimod:

(96) As shown in Table 3, about 10 mg of ozanimod was added into 1.5-mL galss vials followed by adding a certain volume of solvents to form suspensions. These suspensions were stirred at room temperature for 24 hours. The obtained solids were collected and labeled as samples 1-10. Samples 1-10 were identified as Form CS2. The X-ray powder diffraction patterns of these samples are same as FIG. 4, which shows characteristic peaks at 2theta values of 4.0°±0.2°, 13.3°±0.2°, 14.2°±0.2°, 15.9°±0.2°, 17.7°±0.2°, 18.5°±0.2°, 23.2°±0.2°, 26.5°±0.2° and 30.0°±0.2°.

(97) TABLE-US-00004 TABLE 3 Mass Volume Solid Example (mg) Solvent (mL) Form Label 4a 10.2 Acetonitrile 0.5 CS2 Sample 1 4b 10.3 Acetone 0.5 CS2 Sample 2 4c 10.3 Methyl isobutyl ketone 0.5 CS2 Sample 3 4d 10.8 Ethyl acetate 0.5 CS2 Sample 4 4e 9.8 Toluene 0.5 CS2 Sample 5 4f.sup.  9.7 2-Methyltetrahydrofuran 0.5 CS2 Sample 6 4g 10.0 Water 0.5 CS2 Sample 7 4h 10.4 Ethanol/water (19:1, v/v) 0.5 CS2 Sample 8 4i.sup.  9.4 Dimethylformamide/water 0.5 CS2 Sample 9 (3:2, v/v) 4j.sup.  9.7 Acetone/water (9:1, v/v) 0.5 CS2 Sample 10

Example 5

(98) Preparation of Form CS3 of Ozanimod:

(99) About 5.0 mg of ozanimod was added into a 3-mL galss vial followed by adding 0.4 mL of dichloromethane. The mixture was filtered and about 0.2 mg of polymer was added into the clear solution. And then the solution was slowly evaporated at room temperature until white solid was obtained. The obtained white solid was identified as Form CS3.

(100) The XRPD data of the solid prepared in this example are listed in Table 4. The XRPD pattern is displayed in FIG. 7. The DSC curve is displayed in FIG. 8. The TGA curve is displayed in FIG. 9.

(101) TABLE-US-00005 TABLE 4 Relatively 2theta d spacing intensity % 3.04 29.02 12.88 4.43 19.93 100.00 7.84 11.28 16.58 8.92 9.92 10.16 11.03 8.02 15.96 12.96 6.83 83.06 13.43 6.59 11.89 13.72 6.46 33.05 15.80 5.61 3.44 16.57 5.35 5.55 17.00 5.21 19.94 17.98 4.93 4.44 18.38 4.83 4.34 19.83 4.48 6.93 20.06 4.43 8.40 20.57 4.32 5.85 21.53 4.13 7.15 21.98 4.04 6.11 22.56 3.94 8.12 23.17 3.84 23.33 24.09 3.69 14.77 25.14 3.54 12.77 26.00 3.43 41.57 26.68 3.34 9.46 28.42 3.14 6.82 30.67 2.91 1.27 33.98 2.64 0.53 35.51 2.53 0.79

Example 6

(102) Preparation of Form CS3 of Ozanimod:

(103) About 5 mg of ozanimod solid was added into a 3-mL galss vial followed by adding 1.0 mL of acetonitrile. The mixture was filtered and fast evaporated at room temperature until white solid was obtained.

(104) The obtained white solid was identified as Form CS3.The XRPD data of the solid prepared in this example are listed in Table 5. The XRPD pattern is displayed in FIG. 15.

(105) TABLE-US-00006 TABLE 5 Relatively 2theta d spacing intensity % 4.44 19.89 94.06 5.20 16.98 3.53 7.86 11.25 22.55 8.93 9.90 15.72 9.38 9.433 4.17 11.05 8.00 18.33 12.97 6.83 100.00 13.73 6.45 41.96 14.44 6.13 7.95 15.78 5.62 8.10 16.14 5.49 4.53 17.01 5.21 19.74 18.22 4.87 2.42 20.07 4.42 8.54 20.26 4.39 3.28 20.50 4.34 6.66 21.53 4.13 7.83 21.99 4.04 4.91 22.60 3.93 11.03 23.18 3.84 24.17 24.08 3.70 14.26 25.15 3.54 11.64 26.03 3.42 39.79 26.63 3.35 5.94 28.42 3.14 12.28 30.39 2.94 4.29 37.15 2.42 5.92 37.37 2.41 4.67

(106) Use the preparation method of example 6, Form CS3 can be prepared by evaporation in methanol, isopropyl acetate and dimethyl sulfoxide.

Example 7

(107) Preparation of Form CS3 of Ozanimod:

(108) About 15 mg of ozanimod solid was added into a 3-mL galss vial followed by adding 1.0 mL of solvent mixture of glycol dimethyl ether and water (1:1, v/v). The mixture was filtered and slowly evaporated at room temperature until white solid was obtained.

(109) The obtained white solid was identified as Form CS3, which shows characteristic peaks at 2theta values of 4.42°, 5.70°, 7.85°, 11.06°, 12.99°, 17.04°, 23.21°, 24.11° and 26.04°. The XRPD pattern is displayed in FIG. 53.

Example 8

(110) Preparation of Form CS5 of Ozanimod:

(111) About 10 mg of ozanimod solid was added into a 3-mL galss vial followed by adding 2.4 mL of 2-methyltetrahydrofuran. The mixture was filtered and fast evaporated at room temperature to obtain white solid.

(112) The obtained white solid was identified as Form CS5. The XRPD data of the solid prepared in this example are listed in Table 6. The XRPD pattern is displayed in FIG. 10. The DSC curve is displayed in FIG. 11.

(113) TABLE-US-00007 TABLE 6 Relatively 2theta d spacing intensity % 4.25 20.80 100.00 6.76 13.08 3.43 7.71 11.47 1.36 8.55 10.34 13.99 10.79 8.20 1.07 12.96 6.83 34.38 13.61 6.51 9.98 14.42 6.14 1.40 15.13 5.85 1.00 16.39 5.41 3.84 16.86 5.26 4.05 17.29 5.13 2.70 18.37 4.83 0.78 19.57 4.54 2.18 20.48 4.34 5.14 21.60 4.12 8.34 22.52 3.95 1.56 23.20 3.83 1.88 24.04 3.70 4.04 24.98 3.56 4.18 26.03 3.42 5.50 27.06 3.30 3.14 28.35 3.15 0.64 29.00 3.08 0.35 30.27 2.95 0.47 31.14 2.87 0.58 32.77 2.73 0.49 35.24 2.55 0.49 37.31 2.41 0.16

Example 9

(114) Preparation of Form CS6 of Ozanimod:

(115) About 15 mg of ozanimod was weighed into a 3-mL galss vial followed by adding about 0.2 mL of chloroform. The mixture was filtered and fast evaporated at room temperature to obtain white solid.

(116) The obtained white solid was identified as Form CS6. The XRPD data of the solid prepared in this example are listed in Table 7. The XRPD pattern is displayed in FIG. 12.

(117) TABLE-US-00008 TABLE 7 Relatively 2theta d spacing intensity % 4.45 19.88 100.00 7.86 11.24 6.23 8.89 9.95 10.03 11.03 8.02 7.43 13.01 6.81 26.15 13.37 6.62 8.34 13.75 6.44 11.19 14.89 5.95 0.81 15.49 5.72 1.94 15.79 5.61 1.52 16.94 5.23 3.00 17.12 5.18 4.44 17.87 4.96 2.72 19.06 4.66 1.52 19.22 4.62 1.51 20.13 4.41 3.22 21.55 4.12 2.16 22.40 3.97 3.75 22.82 3.90 2.11 23.58 3.77 2.04 24.51 3.63 5.93 25.42 3.50 4.55 26.22 3.40 2.19 26.52 3.36 5.03 27.06 3.30 0.91 27.86 3.20 1.37 28.32 3.15 0.61 28.86 3.09 0.51 30.04 2.97 0.34 32.15 2.78 0.22 33.55 2.67 0.33 37.44 2.40 0.25

(118) Using the preparation method of example 9, Form CS6 can be prepared by evaporating in acetone.

Example 10

(119) Preparation of Form CS6 of Ozanimod:

(120) About 5 mg of ozanimod solid was added into a 3-mL galss vial followed by adding 0.4 mL of chloroform. The mixture was filtered and fast evaporated at room temperature to obtain white solid.

(121) The obtained white solid was identified as Form CS6. The XRPD data of the solid prepared in this example are listed in Table 8. The XRPD pattern is displayed in FIG. 16.

(122) 10 mg of CS6 was re-prepared using the method of example 10, which was used for DSC and TGA characterization. The DSC curve is displayed in FIG. 13. The TGA curve is displayed in FIG. 14.

(123) TABLE-US-00009 TABLE 8 Relatively 2theta d spacing intensity % 4.44 19.88 100.00 7.86 11.25 11.49 8.89 9.94 19.71 11.03 8.02 12.60 13.00 6.81 53.68 13.37 6.62 15.73 13.75 6.44 21.24 14.95 5.93 2.05 15.44 5.74 2.80 15.78 5.62 1.84 17.08 5.19 4.53 17.87 4.96 5.38 19.11 4.64 2.07 20.06 4.43 4.31 21.55 4.12 4.26 22.43 3.96 6.47 23.44 3.80 1.73 24.51 3.63 3.95 25.34 3.51 3.19 26.18 3.40 3.93 26.61 3.35 4.89 27.75 3.22 1.62 28.94 3.09 1.01 30.18 2.96 0.66 32.42 2.76 0.81 36.51 2.46 0.47 37.42 2.40 0.33 38.94 2.31 0.76 39.35 2.29 0.61

Example 11

(124) Preparation of Form CS1 of Ozanimod Hydrochloride:

(125) 10.1 mg of ozanimod hydrochloride was added into a 1.5-mL galss vial followed by adding 0.5 mL of 2-methyltetrahydrofuran to form a suspension. The suspension was stirred at room temperature for 1 week, then white solid was obtained after centrifugation and drying.

(126) The obtained white solid was identified as Form CS1 of ozanimod hydrochloride. The XRPD data of the solid prepared in this example are listed in Table 9. The XRPD pattern is displayed in FIG. 20. The DSC curve is displayed in FIG. 18. The TGA curve is displayed in FIG. 19.

(127) TABLE-US-00010 TABLE 9 Relatively 2theta d spacing intensity % 3.93 22.51 58.37 7.93 11.14 23.15 11.95 7.41 21.69 12.56 7.05 70.18 13.02 6.80 82.51 13.77 6.43 85.16 14.86 5.96 6.06 15.97 5.55 21.05 16.91 5.24 30.15 18.19 4.88 20.42 18.54 4.79 4.12 18.79 4.72 33.76 19.59 4.53 38.99 20.07 4.42 46.27 21.11 4.21 64.20 22.75 3.91 26.66 23.22 3.83 10.34 24.41 3.65 100.00 26.10 3.41 93.31 27.11 3.29 9.18 27.90 3.20 20.23 28.31 3.15 6.44 28.99 3.08 8.18 29.85 2.99 7.60 31.11 2.88 5.90 31.55 2.84 11.45 33.37 2.69 3.80 35.35 2.54 5.57 36.66 2.45 6.89

Example 12

(128) Preparation of Form CS1 of Ozanimod Hydrochloride:

(129) 6.0 mg of ozanimod hydrochloride was added into a 1.5-mL galss vial followed by adding 0.5 mL of methanol. The solution was filtered and evaporated quickly at room temperature for 1 week to obtain solid.

(130) The obtained solid was identified as Form CS1 of ozanimod hydrochloride. The XRPD data of the solid prepared in this example are listed in Table 10. The XRPD pattern is displayed in FIG. 21.

(131) TABLE-US-00011 TABLE 10 Relatively 2theta d spacing intensity % 3.95 22.37 65.70 7.94 11.13 39.57 8.57 10.32 2.24 11.97 7.39 42.06 12.55 7.05 9.32 13.02 6.80 10.98 13.78 6.438 12.03 15.33 5.78 1.81 15.99 5.54 3.50 18.78 4.73 7.47 19.61 4.53 3.45 20.10 4.42 100.00 21.12 4.21 13.94 22.73 3.91 2.92 24.42 3.65 17.01 25.02 3.56 12.72 26.14 3.41 19.94 27.30 3.27 2.47 27.94 3.19 3.98 28.34 3.15 2.68 29.03 3.08 2.70 29.82 3.00 1.74 31.03 2.88 2.53 31.63 2.83 5.10 32.52 2.75 2.27 33.49 2.68 1.55 35.28 2.54 1.87 36.69 2.45 18.83 37.44 2.40 0.94 38.94 2.31 1.26 39.35 2.29 1.87

Example 13

(132) Preparation of Form CS1 of Ozanimod Hydrochloride:

(133) 5.5 mg of ozanimod hydrochloride was added into a 1.5-mL galss vial followed by adding 0.8 mL of solvent mixture of methanol and ethyl acetate (3:1, v/v) and 0.2 mg of polymer. The mixture was fast evaporated at room temperature for 1 week to obtain a solid.

(134) The obtained solid was identified as ozanimod hydrochloride Form CS1. The XRPD data of the solid prepared in this example are listed in Table 11. The XRPD pattern is displayed in FIG. 22.

(135) TABLE-US-00012 TABLE 11 Relatively 2theta d spacing intensity % 3.90 22.64 100.00 7.92 11.16 29.74 10.98 8.06 3.07 11.94 7.41 33.69 12.56 7.05 73.32 13.05 6.78 78.29 13.78 6.43 78.88 14.94 5.93 6.31 16.04 5.52 17.30 16.96 5.23 14.47 18.21 4.87 11.10 18.76 4.73 29.38 19.63 4.53 30.08 20.09 4.42 62.83 21.13 4.20 51.45 22.74 3.91 20.95 24.42 3.65 70.20 24.99 3.56 20.32 26.12 3.41 67.91 27.99 3.19 13.24 29.06 3.07 8.71 29.82 3.00 10.52 31.67 2.83 11.02 35.31 2.54 3.40 36.72 2.45 9.56 39.04 2.31 1.86

Example 14

(136) Preparation of Form CS1 of Ozanimod Hydrochloride:

(137) 5.9 mg of ozanimod hydrochloride solid was added into a 1.5-mL glass vial followed by adding 0.3 mL of dimethylacetamide. The clear solution was placed into a 20-mL glass vial containing 5 mL of tetrahydrofuran for liquid vapor diffusion for 1 week. Then the obtained suspension was filtered and dried to obtain white solid.

(138) The obtained white solid was identified as ozanimod hydrochloride Form CS1. The XRPD data of the solid prepared in this example are listed in Table 12. The XRPD pattern is displayed in FIG. 23.

(139) TABLE-US-00013 TABLE 12 Relatively 2theta d spacing intensity % 3.94 22.42 29.02 7.94 11.13 40.24 8.59 10.30 6.70 10.08 8.78 3.14 11.98 7.39 43.32 12.56 7.05 30.75 13.03 6.79 34.04 13.78 6.42 38.84 15.31 5.79 2.91 15.96 5.55 12.46 16.95 5.23 4.31 17.31 5.12 2.90 18.22 4.87 2.15 18.79 4.72 20.42 19.62 4.52 8.57 20.10 4.42 100.00 21.08 4.22 21.17 22.03 4.04 4.56 22.73 3.91 5.82 24.40 3.65 30.21 25.01 3.56 16.38 25.47 3.50 3.80 26.13 3.41 34.94 26.77 3.33 4.27 27.02 3.30 3.66 27.30 3.27 5.18 27.90 3.20 6.81 29.01 3.08 2.92 29.98 2.98 3.94 31.07 2.88 2.48 31.57 2.83 6.30 32.48 2.76 2.04 32.96 2.72 2.06 34.21 2.62 1.44 35.27 2.54 2.38 36.68 2.45 17.57 38.85 2.32 2.01

Example 15

(140) Preparation of Form CS1 of Ozanimod Hydrochloride:

(141) 5.4 mg of ozanimod hydrochloride was added into a 1.5-mL galss vial followed by adding 0.3 mL of solvent mixture of methanol and water (9:1, v/v) at 50° C. The mixture was filtered and fast cooled at −20° C. to obtain solid.

(142) The obtained white solid was identified as Form CS1 of ozanimod hydrochloride. The XRPD data of the solid prepared in this example are listed in Table 13. The XRPD pattern is displayed in FIG. 24.

(143) TABLE-US-00014 TABLE 13 Relatively 2theta d spacing intensity % 3.92 22.54 56.68 7.94 11.14 51.15 9.36 9.45 1.72 9.89 8.95 3.02 11.96 7.40 51.80 12.57 7.04 11.98 13.04 6.79 15.16 13.79 6.42 12.00 15.96 5.55 3.10 16.95 5.23 3.28 18.21 4.87 4.07 18.78 4.73 9.66 19.69 4.51 12.34 20.08 4.42 100.00 21.11 4.21 27.35 21.87 4.06 5.55 22.77 3.91 7.92 24.40 3.65 44.75 25.00 3.56 10.24 26.13 3.41 43.35 26.80 3.33 6.64 27.91 3.20 6.55 28.96 3.08 3.94 29.86 2.99 2.81 31.57 2.83 7.26 33.39 2.68 2.12 36.71 2.45 15.24

Example 16

(144) Hygroscopicity Assessment of Form CS1 of Ozanimod:

(145) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS1 with about 10 mg of samples. The result is listed in Table 14. The DVS plot is shown in FIG. 25.

(146) TABLE-US-00015 TABLE 14 Crystal Weight gain Form under 80% RH Form CS1 0.36%

(147) The results indicates that the weight gain of Form CS1 under 80% RH is 0.36%. According to the definition of hygroscopicity, Form CS1 belongs to slightly hygroscopic.

Example 17

(148) Hygroscopicity Assessment of Form CS2 of Ozanimod:

(149) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS2 with about 10 mg of samples. The result is listed in Table 15. The DVS plot is shown in FIG. 26.

(150) TABLE-US-00016 TABLE 15 Crystal Weight gain Form under 80% RH Form CS2 0.25%

(151) The results indicates that the weight gain of Form CS2 under 80% RH is 0.25%. According to the definition of hygroscopicity, Form CS2 belongs to slightly hygroscopic.

Example 18

(152) Hygroscopicity Assessment of Form CS3 of Ozanimod:

(153) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS3 with about 10 mg of samples. The result is listed in Table 16. The DVS plot is shown in FIG. 27.

(154) TABLE-US-00017 TABLE 16 Crystal Weight gain Form under 80% RH Form CS3 2.25%

(155) The results indicates that the weight gain of Form CS3 under 80% RH is 2.25%.

Example 19

(156) Hygroscopicity Assessment of Form CS5 of Ozanimod:

(157) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS5 with about 10 mg of samples. The result is listed in Table 17. The DVS plot is shown in FIG. 28.

(158) TABLE-US-00018 TABLE 17 Crystal Weight gain Form under 80% RH Form CS5 0.23%

(159) The results indicates that the weight gain of Form CS5 under 80% RH is 0.23%. According to the definition of hygroscopicity, Form CS5 belongs to slightly hygroscopic.

Example 20

(160) Hygroscopicity Assessment of Form CS6 of Ozanimod:

(161) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS6 with about 10 mg of samples. The result is listed in Table 18. The DVS plot is shown in FIG. 29.

(162) TABLE-US-00019 TABLE 18 Weight gain under 80% Crystal Relative Form Humidity Form CS6 1.68%

(163) The results indicates that the weight gain of Form CS6 under 80% RH is 1.68%.

Example 21

(164) Hygroscopicity Assessment of Form CS1 of Ozanimod Hydrochloride:

(165) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS1 of ozanimod hydrochloride with about 10 mg of samples. The result is listed in Table 19. The DVS plot is shown in FIG. 30.

(166) TABLE-US-00020 TABLE 19 Weight gain under 80% Crystal Relative Form Humidity ozanimod 0.55% hydrochloride Form CS1

(167) The results indicates that the weight gain of Form CS1 of ozanimod hydrochloride under 80% RH is 0.55%. According to the definition standard of hygroscopicity, ozanimod hydrochloride Form CS1 was slightly hygroscopic.

(168) Description and definition of hygroscopicity (Chinese Pharmacopoeia 2015 edition appendix Drug hygroscopic test guidelines, test at 25° C.+/−1° C., 80% RH). deliquescent: Sufficient water is absorbed to form a liquid; very hygroscopic: Increase in mass is equal to or greater than 15 percent; hygroscopic: Increase in mass is less than 15 percent and equal to or greater than 2 percent; slightly hygroscopic: Increase in mass is less than 2 percent and equal to or greater than 0.2 percent. non hygroscopic or almost non hygroscopic: Increase in mass is less than 0.2 percent.

Example 22

(169) Stability Assessment of Form CS1 of Ozanimod:

(170) Three solid samples of Form CS1 were placed in constant temperature and humidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks. XRPD was used to test the crystalline form at the end of week 4. HPLC was used to measure the chemical purity at the end of week 1, 2, and 4. The XRPD comparison result is shown in FIG. 31 (from top to bottom: XRPD pattern of Form CS1 before and after being stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks), and the results are shown in Table 20.

(171) TABLE-US-00021 TABLE 20 Change 1 week 2 week 4 week of the purity purity purity crystalline Initial Form Conditions % % % form Form CS1 25° C./60% RH 99.12 99.18 98.97 No change Form CS1 40° C./75% RH 99.16 99.17 98.92 No change Form CS1 60° C./75% RH 99.26 99.13 98.71 No change

(172) No form change and obvious purity decrease were observed for Form CS1 after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks. The result shows that Form CS1 has good stability.

Example 23

(173) Stability Assessment of Form CS2 of Ozanimod:

(174) Four solid samples of Form CS2 were placed in constant temperature and humidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. XRPD was used to test the crystalline form at the end of week 4. HPLC was used to measure the chemical purity at the end of week 1, 2, and 4. The XRPD comparison result is shown in FIG. 32 (from top to bottom: XRPD pattern of Form CS2 before and after being stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week), and the results are shown in Table 21.

(175) TABLE-US-00022 TABLE 21 Change 1 week 2 week 4 week of the Initial purity purity purity crystalline Form Conditions % % % form Form CS2 25° C./60% RH 99.85 99.63 99.62 No change Form CS2 40° C./75% RH 99.84 99.78 99.55 No change Form CS2 60° C./75% RH 99.91 99.60 99.63 No change Form CS2 80° C. 99.71 N/A N/A No change N/A indicates not tested in this embodiment.

(176) No form change and obvious purity decrease were observed for Form CS2 after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. It can be seen that Form CS2 has good stability.

Example 24

(177) Stability Assessment of Form CS3 of Ozanimod:

(178) Three solid samples of Form CS3 were placed in constant temperature and humidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks. XRPD was used to test the crystalline form at the end of week 4. HPLC was used to measure the chemical purity at the end of week 1, 2, and 4. The XRPD comparison pattern is shown in FIG. 33 (from top to bottom: XRPD pattern of Form CS3 before and after being stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks), and the results are shown in Table 22.

(179) TABLE-US-00023 TABLE 22 Change 1 week 2 week 4 week of the Initial purity purity purity crystalline Form Conditions % % % form Form CS3 25° C./60% RH 99.53 99.30 99.31 No change Form CS3 40° C./75% RH 99.52 99.28 99.17 No change Form CS3 60° C./75% RH 99.36 98.84 98.54 No change

(180) No form change and obvious purity decrease were observed for Form CS3 after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks. It can be seen that Form CS3 has good stability.

Example 25

(181) Stability Assessment of Form CS5 of Ozanimod:

(182) Three solid samples of Form CS5 were placed in constant temperature and humidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 2 weeks. XRPD was used to test the crystalline form at the end of week 4. The XRPD comparison pattern is shown in FIG. 34 (from top to bottom: XRPD pattern of Form CS5 before and after being stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 2 weeks), and the results are shown in Table 23.

(183) TABLE-US-00024 TABLE 23 Change of the Initial crystalline Form Conditions Time form Form CS5 25° C./60% RH 2 weeks No change Form CS5 40° C./75% RH 2 weeks No change Form CS5 60° C./75% RH 2 weeks No change

(184) No form change and obvious purity decrease was observed for Form CS5 after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 2 weeks. It can be seen that Form CS5 has good stability.

Example 26

(185) Stability Assessment of Form CS6 of Ozanimod:

(186) Two samples of Form CS6 were placed in constant temperature and humidity chambers at 25° C./60% RH and 40° C./75% RH for 4 weeks. XRPD was used to test the crystalline form at the end of week 4. HPLC was used to measure the chemical purity at the end of week 1, 2, and 4.The XRPD comparison result is shown in FIG. 35 (from top to bottom: XRPD pattern of Form CS6 before and after being stored under 25° C./60% RH and 40° C./75% RH for 4 weeks), and the results are shown in Table 24.

(187) TABLE-US-00025 TABLE 24 Change 1 week 2 week 4 week of the purity purity purity crystalline Initial Form Conditions % % % form Form CS6 25° C./60% RH 98.44 98.21 98.27 No change Form CS6 40° C./75% RH 98.47 98.33 97.97 No change

(188) No form change and obvious purity decrease were observed for Form CS6 after being stored at 25° C./60% RH and 40° C./75% RH for 4 weeks. It can be seen that Form CS6 has good stability.

Example 27

(189) Stability Assessment of Form CS1 of Ozanimod Hydrochloride:

(190) Four samples of Form CS1 of ozanimod hydrochloride were placed in constant temperature and humidity chambers at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. XRPD was used to test the crystalline form at the end of week 4. HPLC was used to measure the chemical purity at the end of week 1, 2, and 4. The XRPD comparison pattern is shown in FIG. 36 (from top to bottom: XRPD pattern of ozanimod hydrochloride Form CS1 before and after being stored under 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week), and the results are shown in Table 25.

(191) TABLE-US-00026 TABLE 25 Change 1 week 2 week 4 week of the Initial purity purity purity crystalline Form Conditions % % % form Form CS1 of 25° C./60% RH 99.18 99.13 99.22 No change ozanimod hydrochloride Form CS1 of 40° C./75% RH 99.15 99.12 99.24 No change ozanimod hydrochloride Form CS1 of 60° C./75% RH 99.25 99.25 99.36 No change ozanimod hydrochloride Form CS1 of 80° C. 99.34 N/A N/A No change ozanimod hydrochloride

(192) No form change and obvious purity decrease were observed for ozanimod hydrochloride Form CS1 after being stored at 25° C./60% RH, 40° C./75% RH and 60° C./75% RH for 4 weeks and 80° C. for 1 week. It can be seen that Form CS1 of ozanimod hydrochloride has good stability.

Example 28

(193) Particle size distribution:

(194) Certain amount of samples of Form CS1, Form CS2, Form CS3, Form CS5, Form CS6 of ozanimod and Form CS1 of ozanimod hydrochloride were taken for particle size distribution test. The results are shown in Table 26.

(195) TABLE-US-00027 TABLE 26 MV SD D10 D50 D90 Form (μm) (μm) (μm) (μm) (μm) Form CS1 22.40 15.08 3.15 11.20 48.90 Form CS2 23.24 11.21 5.78 14.20 42.35 Form CS3 66.62 39.31 20.36 51.80 130.8 Form CS5 68.84 61.69 6.55 41.10 173.3 Form CS6 68.91 54.79 12.87 46.47 161.7 Form CS1 of 200.7 168.4 20.84 180.8 397.7 ozanimod hydrochloride Mv: Average particle size calculated by volume. SD: Standard deviation D10: particle size which accounts for 10% of the particle size distribution (volume distribution). D50: particle size which accounts for 50% of the particle size distribution (volume distribution), also known as the median diameter. D90: particle size which accounts for 90% of the particle size distribution (volume distribution).

(196) The particle size distribution diagram of Form CS1 is shown in FIG. 37. The result shows that the average particle size of Form CS1 is 22.40 μm, and the particle size distribution is narrow, which presents an almost normal and uniform distribution.

(197) The particle size distribution diagram of Form CS2 is shown in FIG. 38. The result shows that the average particle size of Form CS2 is 23.24 μm, and the particle size distribution is narrow, which presents an almost normal and uniform distribution.

(198) The particle size distribution diagram of Form CS3 is shown in FIG. 39. The result shows that the average particle size of Form CS3 is 66.62 μm, and the particle size distribution is narrow, which presents an almost normal and uniform distribution.

(199) The particle size distribution diagram of Form CS5 is shown in FIG. 40. The result shows that the average particle size of Form CS5 is 68.84 μm, and the particle size distribution is narrow, which presents an almost normal and uniform distribution.

(200) The particle size distribution diagram of Form CS6 is shown in FIG. 41. The result shows that the average particle size of Form CS6 is 68.91 μm, and the particle size distribution is narrow, which presents an almost normal and uniform distribution.

(201) The particle size distribution diagram of Form CS1 of ozanimod hydrochloride is shown in FIG. 42. The result shows that the average particle size of Form CS1 of ozanimod hydrochloride is 200.7 μm, and the particle size is large which conducive to separation during production.

(202) Furthermore, PLM plots of Form CS1, Form CS2, Form CS3, Form CS5, Form CS6 of ozanimod and Form CS1 of ozanimod hydrochloride were displayed in FIG. 43, FIG. 44, FIG. 45, FIG. 46, FIG. 47 and FIG. 48 respectively. Form CS3 was flake-like, Form CS1, Form CS2, Form CS5, Form CS6 and Form CS1 of ozanimod hydrochloride were short rod-like with good dispersion, less agglomeration and uniform particle size.

(203) Uniform particle size helps to simplify the post-treatment process and improve quality control.

Example 29

(204) Solubility Assessment of Form CS1 of Ozanimod and Form CS1 of Ozanimod Hydrochloride:

(205) Form CS1 and Form CS1 of ozanimod hydrochloride were suspended into SGF (Simulated gastric fluids) and FeSSIF (Fed state simulated intestinal fluids, pH=5.0) to obtain saturated solutions. After being equilibrated for 1 h, 4 h and 24 h, concentrations of the saturated solutions were measured by HPLC. The results were listed in Table 27.

(206) TABLE-US-00028 TABLE 27 Solubility (mg/mL) SGF FeSSIF Form CS1 of Form CS1 of Time Form ozanimod Form ozanimod (h) CS1 hydrochloride CS1 hydrochloride 1 6.4 0.2 4.2 1.3 4 6.3 0.2 7.3 1.5 24 5.9 0.2 7.7 1.4

Example 30

(207) Solubility Assessment:

(208) Form CS3 and Form CS5 were suspended into SGF (Simulated gastric fluids) and water, and Form CS2 was suspended into FeSSIF (Fed state simulated intestinal fluids) to obtain saturated solutions. After being equilibrated for 1 h, 4 h and 24 h, concentrations of the saturated solutions were measured by HPLC. The results were listed in Table 28.

(209) TABLE-US-00029 TABLE 28 Solubility (mg/mL) FeSSIF SGF H.sub.2O Time Form Form Form Form Form (h) CS2 CS3 CS5 CS3 CS5 1 2.0 0.54 1.4 0.17 0.24 4 2.2 0.52 1.0 0.24 0.26 24 1.1 0.54 0.77 0.35 0.27

Example 31

(210) Mechanical Stability of Form CS3, Form CS5, Form CS6 of Ozanimod and Form CS1 of Ozanimod Hydrochloride:

(211) Solid samples of Form CS3, Form CS5, Form CS6 of ozanimod and Form CS1 of ozanimod hydrochloride were ground manually for 5 minutes in mortar. The XRPD patterns were displayed in FIG. 49, FIG. 50, FIG. 51 and FIG. 52, respectively (the top pattern is before grinding and bottom pattern is after grinding).

(212) No form change was observed for Form CS3, Form CS5, Form CS6 of ozanimod and Form CS1 of ozanimod hydrochloride under a certain mechanical stress with slightly decrease in crystallinity. Good physical and chemical properties including stability made these forms suitable for drug preparation and storage.

(213) Crystalline forms with better mechanical stability have good physicochemical properties and remain stable under certain mechanical stress. The crystalline drug with better mechanical stability has low requirements on the crystallization equipment, and no special post-treatment condition is required. It is more stable in the formulation process, can significantly reduce the development cost of the drug products, enhance the quality of the drug, and has strong economic value.

(214) It is to be noted that Form CS1 used in Examples 16 to 31 of the present disclosure is prepared by the method of Example 1; Form CS2 is prepared by the method of Example 3; Form CS3 was prepared by the method of Example 6; Form CS5 was prepared by the method of Example 9; Form CS6 was prepared by the method of Example 10; Form CS1 of ozanimod hydrochloride was prepared by the method of Example 11.

(215) The examples described above are only for illustrating the technical concepts and features of the present disclosure, and intended to make those skilled in the art being able to understand the present disclosure and thereby implement it, and should not be concluded to limit the protective scope of this disclosure. Any equivalent variations or modifications according to the spirit of the present disclosure should be covered by the protective scope of the present disclosure