Crystalline forms of selective S1P1 receptor modulator and preparation method thereof

Abstract

The present disclosure relates to crystalline Form 1, Form 2, Form 3 of Ponesimod, a selective S1P1 receptor modulator, and preparation methods thereof. The X-ray powder diffraction pattern of Form 1 shows characteristic peaks at 2theta values of 18.10.2, 14.60.2, 11.30.2; the X-ray powder diffraction pattern of Form 2 shows characteristic peaks at 2theta values of 3.80.2, 10.80.2, 6.10.2; the X-ray powder diffraction pattern of Form 3 shows characteristic peaks at 2theta values of 12.20.2, 6.20.2, 5.60.2. The crystalline forms in present disclosure not only have better stability but also have higher solubility compared with the prior art forms, they are more suitable for the formulation development of Ponesimod.

Claims

1. A crystalline Form 2 of Ponesimod, wherein the X-ray powder diffraction pattern (CuK radiation) shows characteristic peaks at 2theta values of 3.80.2, 10.80.2, and 6.10.2.

2. The crystalline Form 2 according to claim 1, wherein the X-ray powder diffraction pattern further shows one or more characteristic peaks at 2theta values of 5.40.2, 10.20.2, and 7.00.2.

3. The crystalline Form 2 according to claim 1, wherein the X-ray powder diffraction pattern further shows one or more characteristic peaks at 2theta values of 13.70.2, 7.60.2, and 11.40.2.

4. The crystalline Form 2 according to claim 1, wherein the X-ray powder diffraction pattern of Form 2 is substantially as depicted in FIG. 4.

5. A preparation method of Form 2 according to claim 1, wherein the method comprises: mixing Ponesimod with esters to obtain a suspension, and stirring the suspension at a temperature of 0-50 C., isolating solids to obtain Form 2.

6. The preparation method according to claim 5, wherein said ester is isopropyl acetate or ethyl acetate or a combination thereof.

7. A crystalline Form 3 of Ponesimod, wherein the X-ray powder diffraction pattern (CuK radiation) shows characteristic peaks at 2theta values of 12.20.2, 6.20.2, and 5.60.2.

8. The crystalline Form 3 according to claim 7, wherein the X-ray powder diffraction pattern further shows one or more characteristic peaks at 2theta values of 10.80.2, 13.40.2, and 11.20.2.

9. The crystalline Form 3 according to claim 7, wherein the X-ray powder diffraction pattern further shows one or more characteristic peaks at 2theta values of 10.20.2, 16.30.2, and 20.50.2.

10. The crystalline Form 3 according to claim 7, wherein the X-ray powder diffraction pattern of Form 3 is substantially as depicted in FIG. 7.

11. A preparation method of Form 3 according to claim 7, wherein the method is method 1) or method 2): method 1) comprising mixing Ponesimod with esters and firstly heating the mixture to obtain a clear solution, and then cooling until solids are precipitated out, isolating the solids to obtain Form 3; method 2) comprising mixing Ponesimod with ethers to obtain a suspension and stirring the suspension at a temperature of 40-60 C., isolating solids to obtain Form 3.

12. The preparation method according to claim 11, wherein in method 1), said ester is isopropyl acetate or ethyl acetate or a combination thereof; in method 2), said ether is methyl tert-butyl ether.

13. The preparation method according to claim 11, wherein in the method 1), said mixture is heated to 40-80 C. in the heating process; said mixture is cooled to 5 C.-5 C. in the cooling process.

14. A crystalline Form 1 of Ponesimod, wherein the X-ray powder diffraction pattern (CuK radiation) shows characteristic peaks at 2theta values of 18.10.2, 14.60.2, and 11.30.2.

15. The crystalline Form 1 according to claim 14, wherein the X-ray powder diffraction pattern further shows one or more of characteristic peaks at 2theta values of 10.80.2, 16.30.2, 22.70.2, 26.00.2, 6.80.2, and 13.10.2.

16. A preparation method of Form 1 according to claim 14, wherein the method comprises: dissolving Ponesimod into cyclic ethers to obtain a solution, and then adding alkanes into the solution until solids are precipitated out and Form I is obtained.

17. A pharmaceutical composition comprising a therapeutically effective amount of Ponesimod and pharmaceutically acceptable excipients, wherein said Ponesimod is Form 2 according to claim 1.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is used for treatment of psoriasis.

19. A pharmaceutical composition comprising a therapeutically effective amount of Ponesimod and pharmaceutically acceptable excipients, wherein said Ponesimod is Form 3 according to claim 7.

20. A pharmaceutical composition comprising a therapeutically effective amount of Ponesimod and pharmaceutically acceptable excipients, wherein said Ponesimod is Form 1 according to claim 14.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 shows an XRPD pattern of Form 1;

(2) FIG. 2 shows a DSC curve of Form 1;

(3) FIG. 3 shows a TGA curve of Form 1;

(4) FIG. 4 shows an XRPD pattern of Form 2;

(5) FIG. 5 shows a DSC curve of Form 2;

(6) FIG. 6 shows a TGA curve of Form 2;

(7) FIG. 7 shows an XRPD pattern of Form 3;

(8) FIG. 8 shows a DSC curve of Form 3;

(9) FIG. 9 shows an XRPD overlay pattern of Form 2 before and after storage (A is the sample before storage, B is the sample after stored under 25 C./60% RH for 6 months, C is the sample after stored under 40 C./75% RH for 6 months, D is the sample after stored under 80 C. for 3 months);

(10) FIG. 10 shows an XRPD overlay pattern of Form 3 before and after storage (A is the sample before storage, B is the sample after stored under 25 C./60% RH for 6 months, C is the sample after stored under 40 C./75% RH for 6 months).

DETAILED DESCRIPTION OF THE DISCLOSURE

(11) The present disclosure will be further explained by the specific examples, but the present disclosure is not limited to the following examples. The experimental conditions not specified are general conditions. Starting material of Ponesimod used in the preparation method is amorphous prepared by known method in prior art (for example, the method disclosed in CN100567275 C or CN102177144 B).

(12) In the following examples, general conditions or conditions recommended by the manufacturer are used in test methods.

(13) The abbreviations in the present disclosure are explained as follows:

(14) XRPD: X-ray Powder Diffraction;

(15) DSC: Differential Scanning calorimetry;

(16) TGA: Thermal Gravimetric Analysis.

(17) 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 of the present disclosure are as follows:

(18) X-ray Reflection: Cu, K K1 (): 1.540598; K2 (): 1.544426 K2/K1 intensity ratio: 0.50

(19) Voltage: 45 (kV)

(20) Current: 40 (mA)

(21) Scanning range: from 3.0 degree to 40.0 degree

(22) 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 follows:

(23) Heating rate: 10 C./min

(24) Purge gas: nitrogen

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

(26) Heating rate: 10 C./min

(27) Purge gas: nitrogen

Example 1

(28) Preparation Method of Form 1:

(29) 48.1 mg of Ponesimod was added into 0.4 mL of 1, 4-dioxane, then the mixture was filtered to obtain a filtrate. 1.2 mL of n-heptane was added dropwise into the filtrate at room temperature to obtain a suspension, then the suspension was stirred overnight and Form 1 was obtained by centrifugation.

(30) The XRPD data of Form 1 prepared in this example comprise diffraction peaks 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.

(31) TABLE-US-00001 TABLE 1 2theta d spacing intensity % 3.90 22.63 3.82 4.33 20.38 4.11 6.83 12.95 19.68 9.25 9.56 8.92 10.83 8.17 33.57 11.33 7.81 48.18 13.07 6.78 18.63 14.55 6.09 50.30 16.28 5.44 30.46 16.95 5.23 12.05 17.69 5.01 33.34 18.10 4.90 100.00 18.62 4.76 21.41 19.54 4.54 13.20 20.02 4.44 20.89 20.89 4.25 15.98 21.39 4.15 15.31 22.37 3.97 15.94 22.74 3.91 26.48 23.56 3.78 27.53 24.20 3.68 15.26 24.86 3.58 10.25 25.04 3.56 9.56 25.96 3.43 21.58 26.24 3.40 18.40 27.36 3.26 13.49 28.06 3.18 5.96 28.61 3.12 7.59 29.16 3.06 9.02 30.16 2.96 4.41 31.36 2.85 3.55 32.26 2.78 9.03 35.32 2.54 2.65

Example 2

(32) Preparation Method of Form 2:

(33) 399.9 mg of Ponesimod was added into 4.0 mL of ethyl acetate to obtain a suspension. The obtained suspension was stirred at room temperature for 24 hours, and then centrifuged to obtain a solid. The obtained solid was dried under vacuum for 3 hours at room temperature. The obtained solid was Form 2.

(34) The XRPD data of Form 2 prepared in this example comprise the diffraction peaks 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.

(35) TABLE-US-00002 TABLE 2 2theta d spacing Intensity % 3.83 23.05 100.00 5.39 16.40 57.99 6.13 14.42 61.47 7.01 12.61 51.80 7.61 11.62 31.18 8.70 10.17 18.02 9.13 9.68 16.66 9.60 9.22 16.67 10.19 8.68 55.67 10.76 8.22 68.96 11.42 7.75 30.04 12.04 7.35 20.31 12.33 7.18 16.82 12.94 6.84 21.97 13.69 6.47 50.85 14.64 6.05 19.98 15.23 5.82 3.84 17.04 5.20 19.88 18.81 4.72 21.25 20.52 4.33 10.78 22.23 4.00 21.07 23.88 3.73 13.89 24.26 3.67 14.97 25.86 3.45 9.12 29.93 2.99 1.31

Example 3

(36) Preparation Method of Form 3:

(37) 106.8 mg of Ponesimod was added into 2.0 mL of methyl tert-butyl ether to obtain a suspension. The obtained suspension was stirred at 50 C. for 24 hours, and then centrifuged to obtain a solid. The obtained solid was dried under vacuum for 3 hours at room temperature. The obtained solid was Form 3 of Ponesimod.

(38) The XRPD data of Form 3 prepared in this example comprise the diffraction peaks listed in Table 3. The XRPD pattern is displayed in FIG. 7. The DSC curve is displayed in FIG. 8.

(39) TABLE-US-00003 TABLE 3 2theta d spacing Intensity % 3.04 29.06 44.85 4.11 21.47 48.04 5.57 15.86 68.31 6.22 14.21 100.00 6.80 13.00 35.35 7.12 12.42 34.38 8.24 10.73 22.06 8.63 10.25 27.59 9.37 9.44 23.09 9.77 9.05 29.19 10.19 8.68 46.52 10.84 8.16 65.59 11.20 7.90 48.96 11.72 7.55 19.84 12.22 7.24 88.65 12.81 6.91 18.81 13.42 6.60 55.47 13.65 6.49 34.77 14.28 6.20 10.23 14.90 5.95 10.64 16.28 5.45 41.52 17.49 5.07 9.70 18.88 4.70 21.65 19.11 4.64 26.78 19.49 4.55 12.97 20.46 4.34 30.74 21.17 4.20 10.12 21.89 4.06 23.63 22.62 3.93 12.80 23.52 3.78 10.69 24.39 3.65 16.03 24.62 3.62 14.56 25.13 3.54 7.78 26.19 3.40 6.51 27.26 3.27 4.75

Example 4

(40) Preparation Method of Form 3:

(41) 149.5 mg of Ponesimod was added into 1.2 mL of ethyl acetate to obtain a mixture. The mixture was heated to 50 C. to obtain a clear solution, and then the solution was cooled to 4 C. for crystallization, centrifuged to obtain a solid. The solid was dried under vacuum for 3 hours at room temperature. The obtained solid was Form 3 of Ponesimod.

(42) The XRPD data of Form 3 prepared in this example comprise the diffraction peaks listed in Table 4.

(43) TABLE-US-00004 TABLE 4 2theta d spacing Intensity % 5.51 16.03 59.01 6.23 14.19 100.00 6.89 12.82 20.88 8.60 10.28 28.10 9.76 9.06 23.34 10.15 8.71 46.48 10.82 8.18 86.19 11.21 7.89 66.72 12.14 7.29 95.88 13.35 6.63 58.84 16.30 5.44 42.09 18.97 4.68 24.42 20.50 4.33 29.97 21.92 4.06 24.79 24.43 3.64 15.93

Example 5

(44) Stability Assessment of Form 2:

(45) 20 mg of sample of Form 2 was stored under 25 C./60% RH, 40 C./75% RH for 6 months, and 80 C. for 3 months. The assessment results were shown in Table 5. The XRPD patterns of Form 2 before and after storage were depicted in FIG. 9, which show that Form 2 sample doesn't change under 25 C./60% RH and 40 C./75% RH for 6 months, under 80 C. for 3 months. The results indicate that Form 2 has good physical stability.

(46) TABLE-US-00005 TABLE 5 Stability assessment of Form 2 Initial Form Conditions Storage time Solid Form after storage Form 2 25 C./60% RH 6 months Form 2 (FIG. 9A) (FIG. 9B) Form 2 40 C./75% RH 6 months Form 2 (FIG. 9A) (FIG. 9C) Form 2 80 C. 3 months Form 2 (FIG. 9A) (FIG. 9D)

Example 6

(47) Stability Assessment of Form 3:

(48) 20 mg of sample of Form 3 was stored under 25 C./60% RH and 40 C./75% RH for 6 months. The assessment results were shown in Table 6. The XRPD patterns of Form 3 before and after storage were depicted in FIG. 10, which show that Form 3 doesn't change under 25 C./60% RH and 40 C./75% RH for 6 months. The results indicate that Form 3 has good physical stability.

(49) TABLE-US-00006 TABLE 6 Stability assessment of Form 3 Crystalline form after Initial form Conditions Storage time storing Form 3 25 C./60% RH 6 months Form 3 (FIG. 10A) (FIG. 10B) Form 3 40 C./75% RH 6 months Form 3 (FIG. 10A) (FIG. 10C)

Example 7

(50) Solubility assessment of Form 2 in present disclosure and Form A, Form C disclosed in CN102177144B:

(51) Saturated solution of Form 2 and Form A, Form C disclosed in CN102177144B were prepared in FaSSIF (Fasted state simulated intestinal fluids, pH=6.5), FeSSIF (Fed state simulated intestinal fluids, pH=5.0), SGF (Simulated gastric fluids, pH=1.8), and water. Concentrations in the saturation solutions were measured after 1 hour and 24 hours by HPLC. The data were listed in Table 7.

(52) TABLE-US-00007 TABLE 7 Solubility of Form 2 and Form A, Form C disclosed in CN102177144B FaSSIF FeSSIF SGF H.sub.2O Form Form Form Form Form Form Form Form Form Form Form Form Time A C 2 A C 2 A C 2 A C 2 Solubility 1 h 0.007 0.010 0.017 0.141 0.133 0.996 0.034 0.029 0.097 ND* 0.003 ND (mg/mL) 24 h 0.004 0.003 0.033 0.163 0.149 0.813 0.045 0.024 0.124 ND 0.001 ND *ND: below the LOD of instrument

(53) The data in Table 7 indicate that the solubility of Form 2 is higher than that of Form A and Form C in FaSSIF, FeSSIF, and SGF, which means Form 2 will have higher bioavailability, which is of great significance to improve the efficacy and safety of Ponesimod and reduce the drug loading.

Example 8

(54) Solubility assessment of Form 3 and Form A, Form C:

(55) Form 3 and Form A, Form C were prepared into saturated solution in FaSSIF (Fasted state simulated intestinal fluids, pH=6.5), FeSSIF (Fed state simulated intestinal fluids, pH=5.0) and water. Concentrations in the saturation solutions were measured after 1 hour and 24 hours by HPLC. The results were listed in Table 8.

(56) TABLE-US-00008 TABLE 8 Solubility of Form 3 and Form A, Form C disclosed in CN102177144B. FaSSIF FeSSIF H.sub.2O Form Form From From From From From From From Time A C 3 A C 3 A C 3 Solubility 1 h 0.007 0.010 0.084 0.141 0.133 1.168 ND* 0.003 ND (mg/mL) 24 h 0.004 0.003 0.015 0.163 0.149 0.486 ND 0.001 ND *ND: below the LOD of instrument

(57) Solubility is one of the key characteristics of a drug, which directly affects in vivo absorption of the drug. Different crystalline forms have remarkable difference in solubility, and will affect in vivo absorption, thus lead to the differences in bioavailability. As a result, clinical safety and efficacy will be affected.

(58) The data in Table 8 indicate that the solubility of Form 3 is higher than that of Form A and Form C in FaSSIF and FeSSIF, which means Form 3 will have higher bioavailability, which is of great significance to improve the efficacy and safety of Ponesimod and reduce the drug loading.

(59) 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.