CRYSTALLINE FORMS OF ANTIDEPRESSANT DRUG SAGE-217 AND PREPARATION METHOD THEREFOR

Abstract

The present application relates to crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2 of an antidepressant drug SAGE-217 and a preparation method therefor and a pharmaceutical composition containing same. The crystalline form 04 has an XRPD pattern with characteristic peaks at 2theta values of 11.6±0.2°, 13.5±0.2°, 16.2±0.2°, 16.5±0.2°, and 23.2±0.2°; the crystalline form 06 has an XRPD pattern with characteristic peaks at 2theta values of 8.7±0.2°, 10.0±0.2°, 13.2±0.2°, 15.0±0.2°, 15.8±0.2°, and 17.3±0.2°; the crystalline form D-1 has an XRPD pattern with characteristic peaks at 2theta values of 7.2±0.2°, 8.6±0.2°, 13.3±0.2°, 19.6±0.2°, and 23.0±0.2°; and the crystalline form D-2 has an XRPD pattern with characteristic peaks at 2theta values of 7.3±0.2°, 8.6±0.2°, 13.4±0.2°, 19.7±0.2°, and 23.3±0.2°. The novel crystalline forms provided by the present application have good stability, and provide more choices for drug development.

Claims

1. A crystalline form 04 of a compound SAGE-217, the chemical name of SAGE-217 being 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile, wherein it has an X-ray powder diffraction pattern with characteristic peaks at 2theta values of 11.6±0.2°, 13.5±0.2°, 16.2±0.2°, 16.5±0.2°, and 23.2±0.2°.

2. The crystalline form 04 according to claim 1, wherein it has an X-ray powder diffraction pattern with characteristic peaks at 2theta values of 6.8±0.2°, 14.7±0.2°, 18.7±0.2°, 19.2±0.2°, and 21.3±0.2°.

3. The crystalline form 04 according to claim 1, wherein it has an X-ray powder diffraction pattern substantially as depicted in FIG. 1.

4. The crystalline form 04 according to claim 1, wherein the crystalline form 04 is a formic acid solvate of compound SAGE-217.

5. A preparation method for the crystalline form 04 of compound SAGE-217 according to claim 1, wherein it comprises crystallizing SAGE-217 in a formate or a mixed system of formic acid and an organic solvent to obtain the crystalline form 04.

6. The preparation method according to claim 5, wherein the ester group of the formate is selected from groups containing C1-C10, and the organic solvent is selected from alcohols containing C1-C10, dichloromethane and acetonitrile.

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21. A pharmaceutical composition, containing an active ingredient, wherein the active ingredient comprises a crystalline form of a compound SAGE-217 according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0045] FIG. 1 shows the XRPD patterns of crystalline form 04 of Compound I, where A is the XRPD pattern of the crystalline form 04 obtained in Embodiment 1. B is the XPRD pattern of the crystalline form 04 obtained in Embodiment 2, and C and D are the XRPD patterns of the crystalline form 04 obtained in Embodiments 4 and 5;

[0046] FIG. 2 shows the DSC curves of crystalline form 04 of Compound I, where A is the DSC curve of the crystalline form 04 obtained in Embodiment 1, B is the DSC curve of the crystalline form 04 obtained in Embodiment 2, and C is the DSC curve of the crystalline form 04 obtained in Embodiment 4;

[0047] FIG. 3 shows the TGA curves and heat flow curves of crystalline form 04 of Compound I, where A are the TGA curve (upper) and heat flow curve (lower) of the crystalline form 04 obtained in Embodiment 1, B are the TGA curve (upper) and heat flow curve (lower) of the crystalline form 04 obtained in Embodiment 2, and C are the TGA curve (upper) and heat flow curve (lower) of the crystalline form 04 obtained in Embodiment 4;

[0048] FIG. 4 shows the XRPD pattern of crystalline form 06 of Compound I;

[0049] FIG. 5 shows the DSC curve of crystalline form 06 of Compound I;

[0050] FIG. 6 shows the TGA curve (upper) and heat flow curve (lower) of crystalline form 06 of Compound I;

[0051] FIG. 7 shows the XRPD pattern of crystalline form D-1 of Compound I;

[0052] FIG. 8 shows the DSC curve of crystalline form D-1 of Compound I;

[0053] FIG. 9 shows the TGA curve (upper) and heat flow curve (lower) of crystalline form D-1 of Compound I;

[0054] FIG. 10 shows the XRPD pattern of crystalline form D-2 of Compound I;

[0055] FIG. 11 shows the DSC curve of crystalline form D-2 of Compound I;

[0056] FIG. 12 shows the TGA curve (upper) and heat flow curve (lower) of crystalline form D-2 of Compound I;

[0057] FIG. 13 shows an XRPD comparison diagram of the crystalline forms D-1 and D-2 of compound I and the crystalline form D reported in WO2018039378A1;

[0058] FIG. 14 shows the XRPD pattern of crystalline form 01 of Compound I;

[0059] FIG. 15 shows the XRPD pattern of crystalline form 02 of Compound I;

[0060] FIG. 16 shows the XRPD pattern of crystalline form 03 of Compound I;

[0061] FIG. 17 shows the XRPD pattern of crystalline form 05 of Compound I;

[0062] FIG. 18 shows the XRPD pattern of crystalline form 07 of Compound I;

[0063] FIG. 19 shows the XRPD pattern of crystalline form 08 of Compound I;

[0064] FIG. 20 shows the XRPD pattern of crystalline form 09 of Compound I;

[0065] FIG. 21 shows the DVS curve of crystalline form 04 of Compound I;

[0066] FIG. 22 shows the XRPD patterns of crystalline form 04 before and after applying 2 tons of mechanical pressure;

[0067] FIG. 23 shows the XRPD patterns of the patented crystalline form K of WO 2018/039378 A1 before and after applying 2 tons of mechanical pressure.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

[0068] In the following, the present disclosure is further explained by specific embodiments, but they should not be concluded to limit the protective scope of the present disclosure. Those skilled in the art can make improvements to the preparation method and use apparatus within the scope of the claims, and these improvements should also be considered as within the protection scope of the present disclosure. Therefore, the protection scope of the present patent for an invention should be subject to the appended claims.

[0069] In the following embodiments, the test method is usually implemented according to conventional conditions or conditions recommended by the manufacturer; the compound I is prepared by the method of patent WO2014169833.

[0070] The explanations of the abbreviations used in the present disclosure are as follows:

[0071] XRPD: X-ray powder diffraction

[0072] DSC: Differential Scanning Calorimetry

[0073] TGA: Thermogravimetric Analysis

[0074] The X-ray powder diffraction patterns of the present disclosure were collected on a Rigaku Miniflex 600 X-ray diffraction powder diffractometer.

[0075] XRPD scanning parameters: initial position [°2Th.]: 3: end position [°2Th.]: 40; step length of scanning: 0.01°: scanning speed: 10°/min; copper anode (λ=1.54 Å): voltage: 15 mA; current: 40 kV.

[0076] The differential scanning calorimetry (DSC) curves of the present disclosure were collected on a Mettler-Toledo DSC1. The method parameters of differential scanning calorimetry (DSC) were as follows:

[0077] Scan range: 25 to 250° C.: Scan rate: 10° C./min

[0078] Purge gas: nitrogen

[0079] The thermogravimetric analysis (TGA) curves of the present disclosure were collected on a Mettler-Toledo TGA/DSC1.

[0080] The method parameters of thermogravimetric analysis (TGA) were as follows:

[0081] Scan range: 25 to 320° C.: Scan rate: 10° C./min

[0082] Purge gas: nitrogen

[0083] In the following, the implementation of the present application is described through embodiments, and those skilled in the art should realize that these specific embodiments only show the implemented technical solutions selected to achieve the purpose of this application, and are not limitations on the technical solutions. According to the teachings of this application, it is obvious that the improvement of the technical solution of this application in combination with the existing technology is obvious, and they all fall within the protection scope of the present application.

Example 1: Preparation of Crystalline Form 04 of Sage-217

[0084] A 10 mg/mL ethyl formate solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate stood at 10° C. and was filtered to give a white solid, whose XRPD spectrum is shown as a spectral line A in FIG. 1, and the corresponding XRPD data is as follows:

TABLE-US-00001 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 6.8° 13.0 14.9 11.6° 7.6 100.0 13.5° 6.6 47.5 14.7° 6.0 19.5 16.2° 55 20.8 16.5° 5.4 24.3 18.7° 4.7 20.9 19.2° 4.6 25.1 21.3° 4.2 24.5 23.2° 3.8 33.0

Example 2 (Repeat the Operation of Example 1)

[0085] A 10 mg/mL ethyl formate solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate stood at 10° C. and was filtered to give a white solid, whose XRPD spectrum is shown as a spectral line B in FIG. 1.

Example 3: Preparation of Crystalline Form 04 of Sage-217

[0086] A 25 mg/mL ethyl formate solution of Sage-217 was prepared, the solution was stirred at 25° C. for 6 h to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate stood at 25° C. and was filtered to give a white solid, whose XRPD spectrum is consistent with FIG. 1A.

Example 4: Preparation of Crystalline Form 04 of Sage-217

[0087] A 10 mg/mL formic acid/isobutanol (1/1, V/V) solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 25° C. and was filtered to give a white solid, whose XRPD spectrum is shown as a spectral line C in FIG. 1.

Example 5: Preparation of Crystalline Form 04 of Sage-217

[0088] A 10 mg/mL formic acid/isobutanol (1/1. V/V) solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 40° C. and was filtered to give a white solid, whose XRPD spectrum is shown as a spectral line D in FIG. 1.

Example 6: Preparation of Crystalline Form 06 of Sage-217

[0089] A 10 mg/mL nitromethane solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 25° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 4, and the corresponding XRPD data is as follows:

TABLE-US-00002 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 5.0° 17.8 16.1 5.5° 16.0 9.3 8.7° 10.2 52.2 10.0° 8.9 42.4 13.2° 6.7 86.9 15.0° 5.9 100.0 15.8° 5.6 55.9 17.3° 5.1 49.1 19.4° 4.6 34.9 20.0° 4.4 32.5 21.9° 4.1 11.4

Example 7: Preparation of Crystalline Form 06 of Sage-217

[0090] A 10 mg/mL nitromethane solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 40° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 4.

Example 8: Preparation of Crystalline Form D-1 of Sage-217

[0091] A 10 mg/mL 4-methyl-2-pentanone solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 25° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 7, and the corresponding XRPD data is as follows:

TABLE-US-00003 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.2° 12.3 100.0 7.9° 11.3 8.1 8.6° 10.2 13.0 10.6° 8.3 4.7 13.3° 6.6 19.8 15.7° 5.7 3.7 16.3° 5.4 7.6 19.6° 4.5 23.5 21.3° 4.2 6.3 21.6° 4.1 7.1 23.0° 3.9 7.0

Example 9: Preparation of Crystalline Form D-1 of Sage-217

[0092] A 10 mg/mL 4-methyl-2-pentanone solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 40° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 7.

Example 10 (Repeat the Operation of Example 9)

[0093] A 10 mg/mL 4-methyl-2-pentanone solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 40° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 7.

Example 11: Preparation of Crystalline Form D-2 of Sage-217

[0094] A 10 mg/mL 4-methyl-2-pentanol/isobutyl acetate (1/1, v/v) solution of Sage-217 was prepared, the solution was stirred at 25° C. for 60 mini to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 25° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 10, and the corresponding XRPD data is as follows:

TABLE-US-00004 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.3° 12.2 100.0 7.8° 11.3 42.1 8.6° 10.3 63.5 10.6° 8.3 18.2 13.4° 6.6 79.3 15.5° 5.7 32.6 16.4° 5.4 28.9 19.0° 4.7 28.1 19.7° 4.5 66.3 21.3° 4.2 35.1 23.3° 3.8 44.6 31.3° 2.9 7.0

Example 12: Preparation of Crystalline Form D-2 of Sage-217

[0095] A 10 mg/mL 4-methyl-2-pentanone/isobutyl acetate (1/1, v/v) solution of Sage-217 was prepared, the solution was stiffed at 25° C. for 60 min to dissolve completely, and filtered with an organic filter head (25 mm/0.45 μm), and the resulting filtrate was crystallized under reduced pressure at 40° C. and was filtered to give a white solid, whose XRPD spectrum is shown in FIG. 10.

Example 13: DVS Test of Crystalline Form 04 of Sage-217

[0096] The sample of crystalline form 04 prepared in Example 1 was placed on a microbalance plate in a sealed sample chamber, and then exposed to different relative humidity, the relative humidity ranged from 0 ft. or 40% to 90%, and changed in 10% increments. At each humidity level, the sample is balanced when dm/dt is less than 0.002% within 10 minutes. The mass of the dried sample and the equilibrium mass at each humidity level were recorded, and the weight change was plotted against relative humidity, which is the moisture adsorption isotherm of the sample. See FIG. 21 for the results.

[0097] It can be seen from FIG. 21 that when the relative humidity changed from 40%/0 to 90% in the crystalline form 04 at 25° C., the water absorption of the crystalline form 04 is 0.06%, indicating that the crystalline form 04 has no or almost no hygroscopicity.

[0098] Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Appendix XIX J of Chinese Pharmacopoeia 2010 Edition, Guidelines for Hygroscopicity, with experimental conditions: 25±1° C., 80% relative humidity):

[0099] Deliquescent: sufficient water is absorbed to form liquid

[0100] Extremely hygroscopic: the increase in mass is not less than 15%

[0101] Hygroscopic: the increase in mass is less than 15% but not less than 2%

[0102] Slightly hygroscopic: the increase in mass is less than 2% but not less than 0.2%

[0103] Practical nonhygroscopic: the increase in mass is less than 0.2%.

Example 14: Stability of Crystalline Form 04 Under Different Temperature and Humidity Conditions

[0104] The samples of crystalline form 04 prepared in Example 1 were taken, and placed at 25° C./60% humidity and 40° C./75% humidity for 1 month; placed at 2-8° C. for 9 months: after the placement, the above-mentioned samples were taken out and tested for the crystalline form. The results are shown in the following table.

TABLE-US-00005 Temperature 25° C. 40° C. 2-8° C. (in freezer) Relative humidity 60% 75% / Storage time 1 month 1 month 9 months Crystalline form Crystalline Crystalline Crystalline form 04 form 04 form 04

[0105] Samples of the crystalline form 04 of the present disclosure were taken and placed at 2-8° C. for 9 months, and performed purity determination by high performance liquid chromatography before and after placement to evaluate chemical stability. The purity results of high performance liquid chromatography are shown in the following table. The results show that the crystalline form 04 has good chemical stability.

TABLE-US-00006 HPLC purity Test time Example 1 Example 2 Before storage 97.7% 98.5% After storage for 9 months 97.5% 98.2%

Example 15: Stability Experiment of Crystalline Form D-1

[0106] The crystalline form D-1 prepared in Example 8 was placed at 2-8° C. and after 9 months of storage, it was taken out to evaluate chemical stability, and the results showed that the crystalline form did not change. Samples of the crystalline form D-1 prepared by the present disclosure were taken and placed at 2-8° C. for 9 months, and performed purity determination by high performance liquid chromatography before and after placement to evaluate chemical stability. The purity results of high performance liquid chromatography are shown in the following table. The results show that the crystalline form D-1 has good chemical stability.

TABLE-US-00007 HPLC purity Test time Example 8 Example 9 Before storage 99.1% 99.4% After storage for 9 months 98.8% 99.2%

Example 16: Stability Experiment of Crystalline Form D-2

[0107] Samples of the crystalline form D-2 prepared by the present disclosure were taken and placed at 2-8° C. for 9 months, and performed purity determination by high performance liquid chromatography before and after placement to evaluate chemical stability. The purity results of high performance liquid chromatography are shown in the following table. In 9 months of storage at a temperature of 2-8° C., the chemical stability is good.

TABLE-US-00008 HPLC purity Test time Example 11 Example 12 Before storage 99.1% 99.2% After storage for 9 months 98.7% 98.9%

Example 17: Thermodynamic Solubility and Mechanical Pressure Stability Tests of Crystalline Form 04

[0108] Thermodynamic solubility test: the solid powder was added to water to a saturated solution, and then the suspension liquid was stirred under magnetic stirring at 25° C. for 24 hours. After completion, it was filtered with a 0.20 μm filter and analyzed by HPLC. Tests were carried out in parallel, and each group was tested twice to take the average.

TABLE-US-00009 Crystalline form 04 Crystalline form K Area Concentration Area Concentration Group (mAu*s) (ng/mL) (mAu*s) (ng/mL) Group 1 12.6 450.6 10.9 392.7 Group 2 11.8 424.3 11.2 403.2 Average 12.2 437.5 11.1 398.0

[0109] The thermodynamic dissolution results are recorded in the table above. Based on the results of these samples, the thermodynamic solubility was calculated. The value of crystalline form 04 is 437.5 ng/mL, the value of crystalline form K is 398.0 ng/mL, and the thermodynamic solubility of the two was within the error range, and the results were basically the same.

[0110] To further evaluate the mechanical stability of the crystalline form 04 of the present application and the crystalline form K reported in WO 2018/039378 A1, a 100 mg sample was subjected to 2 tons of mechanical pressure, and the recovered tablets were gently ground and tested by XRPD.

[0111] The XRPD test of crystalline form 04 showed no obvious change (FIG. 22), while for the reported crystalline form K in WO 2018/039378 A1, a slight decrease in its crystallinity was observed (FIG. 23). From one side, it shows that the physical stability of the crystalline form 04 of this application is better than that of the crystalline form K.

Example 18: Preparation of Crystalline Form 01 of Sage-217

[0112] A 10 mg/mL p-xylene solution of Sage-217 was prepared, cooled from 75° C. to 25° C. stirred to crystallize, filtered to give a solid, which was tested by XRPD, the XRPD pattern is shown in FIG. 14, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2.

TABLE-US-00010 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.5 11.8 17.4 10.4 8.5 29.9 10.6 8.4 13.5 14.9 5.9 100.0 15.1 5.9 40.1 20.9 4.3 58.8 22.4 4.0 67.2 22.5 4.0 69.8 30.0 3.0 13.9 30.1 3.0 13.1

Example 19: Preparation of Crystalline Form 02 of Sage-217

[0113] A 10 mg/mL ethanediamine solution of Sage-217 was prepared, cooled from 50° C. to 25° C. under stirring to crystallize, and filtered to give a solid and dried to test by XRPD, the XRPD pattern is shown in FIG. 15, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline

TABLE-US-00011 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.2 12.2 4.3 9.3 9.5 10.3 10.8 8.2 26.0 11.0 8.1 24.2 11.2 7.9 19.6 12.1 7.3 27.0 14.5 6.1 100.0 17.3 5.1 33.0 17.7 5.0 21.9 19.3 4.6 25.8 19.5 4.5 27.4 20.2 4.4 22.9 21.5 4.1 20.8 22.4 4.0 22.4 22.9 3.9 22.0

Example 20: Preparation of Crystalline Form 03 of Sage-217

[0114] A 10 mg/mL diethyl carbonate solution of Sage-217 was prepared, cooled from 75° C. to 25° C., stirred to crystallize, filtered to give a solid, which was tested by XIWD, the XRPD pattern is shown in FIG. 16, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2.

TABLE-US-00012 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.0 12.6 38.1 7.7 11.4 36.3 9.9 8.9 23.4 10.9 8.2 46.3 15.3 5.8 76.5 15.4 5.7 100.0 16.6 5.4 16.3 17.9 5.0 31.0 18.8 4.7 49.0 21.7 4.1 97.7 23.2 3.8 62.7

Example 21: Preparation of Crystalline Form 05 of Sage-217

[0115] A 10 mg/mL glycol dimethyl ether slurry of Sage-217 was prepared, stirred at 25° C. for 15 days, filtered to give a solid, which was tested by XRPD, the XRPD pattern is shown in FIG. 17, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2.

TABLE-US-00013 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.0 12.6 36.6 8.5 10.4 6.5 10.4 8.5 100.0 13.0 6.8 12.2 15.4 5.8 9.9 16.9 5.2 17.7 18.6 4.8 38.4 20.8 4.3 14.1 22.3 4.0 30.7 23.4 3.8 13.6 25.7 3.5 24.4 25.8 3.5 20.0

Example 22: Preparation of Crystalline Form 07 of Sage-217

[0116] A 10 mg/mL methylbenzene solution of Sage-217 was prepared, cooled from 75° C. to 10° C., stirred to crystallize, filtered to give a solid, which % w tested by XRPD, the XRPD pattern is shown in FIG. 18, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2.

TABLE-US-00014 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.0 12.6 100.0 10.5 8.4 77.5 16.2 5.5 25.6 18.6 4.8 14.8 21.1 4.2 83.4 22.7 3.9 21.7 26.5 3.4 8.5 26.6 3.4 6.8 28.2 3.2 11.2 29.6 3.0 12.5

Example 23: Preparation of Crystalline Form 08 of Sage-217

[0117] A 0.10 mg/mL methylbenzene solution of Sage-217 was prepared, rapidly cooled from 75° C. to 10° C., stirred to crystallize, filtered to give a solid, which was tested by XRPD, the XRPD pattern is shown in FIG. 19. The corresponding XRPD data is as follows.

TABLE-US-00015 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 4.6 19.0 10.7 5.0 17.6 7.6 6.3 13.9 13.6 7.7 11.5 100.0 8.1 10.9 41.4 10.7 8.3 10.2 11.5 7.7 30.0 12.6 7.0 17.1 13.1 6.8 10.4 13.7 6.5 15.2 13.8 6.4 15.0 14.3 6.2 17.6 15.1 5.9 23.1 15.2 5.8 30.5 15.5 5.7 19.0 16.0 5.5 10.1 16.7 5.3 10.5 17.0 5.2 12.9 17.8 5.0 11.6 17.9 4.9 37.3 18.8 4.7 17.7 18.9 4.7 15.1 19.1 4.6 14.3 19.3 4.6 25.9 19.7 4.5 36.7 21.4 4.1 10.5 25.3 3.5 7.9

Example 24: Preparation of Crystalline Form 09 of Sage-217

[0118] A 10 mg/mL acetonitrile solution of Sage-217 was prepared, cooled from 50° C. to 25° C. stirred to crystallize, filtered to give a solid, which was tested by XRPD, the XRPD pattern is shown in FIG. 20, and the corresponding XRPD data is as follows. In practice, it is found that the stability of this crystalline form is poorer than the aforementioned crystalline form 04, crystalline form 06, crystalline form D-1, and crystalline form D-2.

TABLE-US-00016 Position [2θ] (±0.2°) D spacing [Å] Relative intensity [%] 7.6 11.6 100.0 7.8 11.4 43.0 15.2 5.8 78.5 15.3 5.8 36.9 17.3 5.1 10.1 22.8 3.9 37.7 22.9 3.9 29.2 30.6 2.9 10.2

[0119] This application includes but is not limited to the above embodiments. Any equivalent substitution or partial improvement made under the principle of the spirit of this application will be considered to be within the protection scope of this application.