Crystal form of ozanimod hydrochloride and processes for preparation therefor

Abstract

The present disclosure relates to crystalline form CS3 of ozanimod hydrochloride which can be used for treating autoimmune diseases, particularly used for preparing drugs for treating multiple sclerosis and ulcerative colitis and preparation method thereof. ##STR00001##

Claims

1. A crystalline form CS3 of ozanimod hydrochloride, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2 theta values of 19.60.2, 24.90.2 and 5.80.2 using CuK radiation.

2. The crystalline form CS3 of ozanimod hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2 theta values of 7.80.2, 11.70.2 and 29.50.2 using CuK radiation.

3. The crystalline form CS3 of ozanimod hydrochloride according to claim 1, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2 theta values of 3.90.2, 14.20.2 and 20.70.2 using CuK radiation.

4. A process for preparing crystalline form CS3 of ozanimod hydrochloride according to claim 1, wherein the process comprises: dissolving ozanimod hydrochloride into ethanol or a mixture of solvents selected from an alcohol and an arene, an alcohol and a nitrile, an alcohol and an acid, an acid and water, filtering and adding a polymer into the solution and then evaporating at room temperature to obtain a white solid.

5. The process for preparing crystalline form CS3 of ozanimod hydrochloride according to claim 4, wherein each said alcohol is methanol or ethanol; each said acid is acetic acid; said arene is toluene; said nitrile is acetonitrile.

6. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS3 of ozanimod hydrochloride according to claim 1 and a pharmaceutically acceptable carrier, a diluent or an excipient.

7. A method for treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form CS3 of ozanimod hydrochloride according to claim 1.

8. A method for treating multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form CS3 of ozanimod hydrochloride according to claim 1.

9. The crystalline form CS3 of ozanimod hydrochloride according to claim 2, wherein the X-ray powder diffraction pattern shows one or two or three characteristic peaks at 2 theta values of 3.90.2, 14.20.2 and 20.70.2 using CuK radiation.

10. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS3 of ozanimod hydrochloride according to claim 9 and a pharmaceutically acceptable carrier, a diluent or an excipient.

11. A method for treating ulcerative colitis, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form CS3 of ozanimod hydrochloride according to claim 9.

12. A method for treating multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form CS3 of ozanimod hydrochloride according to claim 9.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows an XRPD pattern of Form CS3 in Example 1

(2) FIG. 2 shows a DSC curve of Form CS3 in Example 1

(3) FIG. 3 shows a TGA curve of Form CS3 in Example 1

(4) FIG. 4 shows a .sup.1H NMR spectrum of Form CS3 in Example 1

(5) FIG. 5 shows a DVS plot of Form CS3 in Example 2

(6) FIG. 6 shows a PSD diagram of Form CS3 in Example 4

(7) FIG. 7 shows a PLM image of Form CS3 in Example 4

(8) FIG. 8 shows an XRPD pattern overlay of Form CS3 before and after stability assessment in Example 5

DETAILED DESCRIPTION OF THE DISCLOSURE

(9) 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.

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

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

(12) XRPD: X-ray Powder Diffraction

(13) DSC: Differential Scanning calorimetry

(14) TGA: Thermal Gravimetric Analysis

(15) DVS: Dynamic Vapor Sorption

(16) PSD: Particle Size Distribution

(17) PLM: Polarized Light microscopy

(18) 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:

(19) X-ray Reflection: Cu, K

(20) K1 (): 1.540598; K2 (A): 1.544426

(21) K2/K1 intensity ratio: 0.50

(22) Voltage: 45 (kV)

(23) Current: 40 (mA)

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

(25) 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:

(26) Heating rate: 10 C./min

(27) Purge gas: nitrogen

(28) Thermal gravimetric analysis (TGA) data in the present disclosure were acquired by a TA Q500. The parameters of the thermal gravimetric analysis (TGA) method of the present disclosure were as follow:

(29) Heating rate: 10 C./min

(30) Purge gas: nitrogen

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

(32) Temperature: 25 C.

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

(34) dm/dt: 0.002%/min

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

(36) 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:

(37) 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.

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

Example 1

(39) Preparation of Form CS3 of Ozanimod Hydrochloride

(40) Certain amount of ozanimod hydrochloride solid was weighed into a 3.0-mL glass vial, and corresponding volume of solvent in Table 1 was added to dissolve the solid. Then the mixture was filtered and approximately 0.2 mg of polymer was added into the clear solution, and then the mixture was evaporated slowly at room temperature to obtain white solid.

(41) TABLE-US-00002 TABLE 1 Sample Weight (mg) Solvent (v:v) Volume (mL) 1-a 20.3 Methanol/Ethyl acetate 3:1 6.0 1-b 5.0 Ethanol 1.6 1-c 5.3 Acetic acid/Water 9:1 0.5 1-d 5.3 Methanol/Toluene 3:1 0.5 1-e 5.3 Methanol/Acetic acid 1:1 0.8 1-f 5.0 Methanol/Acetonitrile 2:1 0.5

(42) The obtained solids were confirmed to be Form CS3. The XRPD data of the solid obtained in example 1-a are listed in Table 2. The XRPD pattern is substantially as depicted displayed in FIG. 1. The DSC curve shows the first endothermic peak when heated to around 93 C., and shows the second endothermic peak when heated to around 234 C., which is substantially as depicted in FIG. 2. The TGA curve of Form CS3 shows about 1.7% weight loss when heated to 150 C., which is substantially as depicted in FIG. 3. The .sup.1H NMR spectrum of the solid is substantially as depicted in FIG. 4, and relevant data are as follows: .sup.1H NMR (400 MHz, DMSO) 9.54 (d, J=31.2 Hz, 2H), 8.49 (d, J=2.2 Hz, 1H), 8.39 (dd, J=9.0, 2.2 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.55 (dd, J=8.5, 6.0 Hz, 2H), 5.31 (t, J=5.0 Hz, 1H), 5.07-4.81 (m, 2H), 3.84-3.66 (m, 2H), 3.59-3.43 (m, 1H), 3.31-3.15 (m, 1H), 3.03 (d, J=22.5 Hz, 2H), 2.64-2.44 (m, 1H), 2.38-2.24 (m, 1H), 1.39 (d, J=6.0 Hz, 6H).

(43) TABLE-US-00003 TABLE 2 2Theta d Spacing Relative Intensity % 3.90 22.66 82.52 5.83 15.16 49.50 7.78 11.36 95.14 9.77 9.05 18.03 11.71 7.56 29.74 12.83 6.90 26.10 13.67 6.48 31.07 14.20 6.24 38.94 14.61 6.06 31.92 15.62 5.67 16.16 17.20 5.15 11.10 18.26 4.86 11.09 19.13 4.64 45.87 19.63 4.52 100.00 20.70 4.29 24.09 21.24 4.18 41.26 22.27 3.99 18.51 22.85 3.89 28.99 23.28 3.82 23.29 24.44 3.64 47.51 24.93 3.57 41.07 25.60 3.48 14.86 27.42 3.25 18.32 27.81 3.21 21.56 28.35 3.15 22.01 29.57 3.02 23.44 30.10 2.97 25.93 31.35 2.85 14.86 31.88 2.81 9.34 32.78 2.73 4.26 33.69 2.66 4.06 35.68 2.52 10.65 37.74 2.38 5.21

Example 2

(44) Hygroscopicity Assessment of Form CS3 of Ozanimod Hydrochloride:

(45) Dynamic vapor sorption (DVS) was applied to test hygroscopicity of Form CS3 with about 10 mg of sample. The result is listed in Table 3. The DVS plot is substantially as depicted in FIG. 5.

(46) TABLE-US-00004 TABLE 3 Solid Form Weight Gain under 80% RH Form CS3 of ozanimod hydrochloride 2.50%

(47) The result indicates that the weight gain of Form CS3 under 80% RH is 2.50%. According to the definition of hygroscopicity, Form CS3 is hygroscopic. The low hygroscopicity meets the requirement of medicine.

(48) 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%; hygroscopic: Increase in mass is less than 15% and equal to or greater than 2%; slightly hygroscopic: Increase in mass is less than 2% and equal to or greater than 0.2%. no or almost no hygroscopic: Increase in mass is less than 0.2%.

Example 3

(49) Solubility Assessment of Form CS3 of Ozanimod Hydrochloride:

(50) Form CS3 of ozanimod hydrochloride was suspended into SGF (Simulated gastric fluids, pH=1.8), FeSSIF (Fed state simulated intestinal fluids, pH=5.0) and water 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 are listed in Table 4.

(51) TABLE-US-00005 TABLE 4 Solubility (mg/mL) Time (h) SGF FeSSIF H.sub.2O 1 0.2 2.1 1.1 4 0.2 2.1 1.4 24 0.2 1.8 1.3

(52) The results show that Form CS3 of ozanimod hydrochloride has good solubility in SGF, FeSSIF and H.sub.2O, which is beneficial to improve the bioavailability of the drug. Solubility is one of the key properties of drugs, which affects drug absorption in body directly. As the solubility of different crystalline drugs may be obviously different, the absorption dynamic in body may change, which results in the difference in bioavailability and ultimately affects the clinical safety and efficacy of drugs. Therefore, Form CS3 of ozanimod hydrochloride of the present disclosure has superior effects in solubility.

Example 4

(53) Particle Size Distribution and Morphology Study:

(54) Sample of Form CS3 was taken for particle size distribution test. The results are shown in Table 5.

(55) TABLE-US-00006 TABLE 5 Solid Form MV(m) SD D10 (m) D50 (m) D90 (m) Form CS3 of 131.8 107.7 19.94 100.5 287.0 ozanimod hydrochloride

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

(57) Mv: Average particle size calculated by volume.

(58) D10: particle size which accounts for 10% of the particle size distribution (volume distribution).

(59) D50: particle size which accounts for 50% of the particle size distribution (volume distribution), also known as the median diameter.

(60) D90: particle size which accounts for 90% of the particle size distribution (volume distribution).

(61) The particle size distribution (PSD) diagram and polarized Light microscopy (PLM) image of Form CS3 are substantially as depicted in FIG. 6 and FIG. 7. The result shows that the average particle size of Form CS3 is 131.8 and the particle size distribution is narrow and uniform, which presents an almost normal distribution. Furthermore, the PLM image shows that Form CS3 is flaky with good dispersion.

Example 5

(62) Stability Assessment of Form CS3 of Ozanimod Hydrochloride:

(63) Two samples of Form CS3 of ozanimod hydrochloride were placed in constant temperature and humidity chambers at 25 C./60% RH and 40 C./75% RH for 2 weeks. XRPD was used to test the crystalline form. The XRPD overlay pattern is substantially as depicted in FIG. 8 (from top to bottom: XRPD pattern of Form CS3 before and after being stored under 25 C./60% RH and 40 C./75% RH for 2 weeks). No form change was observed for Form CS3 after being stored at 25 C./60% RH and 40 C./75% RH for 2 weeks. It can be seen that Form CS3 of ozanimod hydrochloride has good stability, which is benefit for drug storage.

(64) 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.