CRYSTALLINE FORMS OF 5alpha-ANDROSTANE-3beta,5,6beta-TRIOL AND PREPARATION METHODS THEREFOR

Abstract

The present invention relates to four crystalline forms (crystalline forms A, B, C and D) of 5-androstane-3,5,6-triol (YC-6) and preparation methods therefor. The four crystalline forms have significant difference in their lattice parameters, 2 values and intensity in X-ray power diffraction, and melting points, etc. The study on its polymorphism is very important for further studying its effect, bioavailability and stability.

Claims

1-9. (canceled)

10. A crystalline form of 5o-androstane-3,5,6-triol, wherein the crystalline form is a transparent column-shaped crystal, and belongs to orthorhombic crystal system and space group P2.sub.12.sub.12.sub.1, and wherein the crystalline form is characterized by lattice parameters of a=6.30.2 , b=12,60,2 , c=26.70.2 , =90.0, =90, =90.0; and characterized by diffraction peaks at diffraction angle 2 values of 4,00.2, 8.10.2, 8.5+0.2, 9,40.2, 12.50.2, 14.00,2, 14.90.2, 15.50.2, 16.40.2, 17.1 0.2, 18.30.2, 19.50.2, 20.50.2, 20.90.2, 21.50.2 degrees; and characterized by an endothermic transition temperature of 2262 C.

11. A method for preparing the crystalline form of claim 10, comprising: dissolving 5-androstane-3,5,6-triol in tetrahydrofuran at room temperature, with a ratio of the 5-androstane-3,5,6-triol to the tetrahydrofuran being 1 g : 1030 mL; adding tetrahydrofuran in a ratio of 05:1 to dilute; and allowing to form a crystalline precipitate.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 shows the X-ray single crystal diffraction diagrams of crystalline form A of YC-6.

[0019] FIG. 2 shows the X-ray powder diffraction diagrams of crystalline form A of YC-6.

[0020] FIG. 3 shows the differential thermal analysis diagrams of crystalline form A of YC-6.

[0021] FIG. 4 shows the X-ray single crystal diffraction diagrams of crystalline form B of YC-6.

[0022] FIG. 5 shows the X-ray powder diffraction diagrams of crystalline form B of YC-6.

[0023] FIG. 6 shows the differential thermal analysis diagrams of crystalline form B of YC-6.

[0024] FIG. 7 shows the X-ray single crystal diffraction diagrams of crystalline form C of YC-6.

[0025] FIG. 8 shows the X-ray powder diffraction diagrams of crystalline form C of YC-6.

[0026] FIG. 9 shows the differential thermal analysis diagrams of crystalline form C of YC-6.

[0027] FIG. 10 shows the X-ray single crystal diffraction diagrams of crystalline form D of YC-6.

[0028] FIG. 11 shows the X-ray powder diffraction diagrams of crystalline form D of YC-6.

[0029] FIG. 12 shows the differential thermal analysis diagrams of crystalline form D of YC-6.

DETAILED DESCRIPTION OF THE INVENTION

[0030] Physical Characterization

[0031] X-ray single crystal diffraction diagrams for different crystalline forms of YC-6, which were obtained by the examples, were obtained using Xcalibur Nova biomacromolecule X-Ray single crystal diffractometer (Agilent Technologies (China) Co., Ltd), under the following settings: fixed target of copper; output power: 50 W, two-dimensional surface detecting system: 165 mmCCD; resolution: 0.005 degree; cooling nitrogen: 180+25 C.; control accuracy: 0.5 C.; test temperature: 150 k.

[0032] X-ray powder diffraction diagrams for different crystalline forms of YC-6, which were obtained by the examples, were obtained using D/Max-IIIA X-ray powder diffractometer (Rigaku, Japan), under the following settings: fixed target of copper; power: 3 kW; detecting angle: 150, sensitivity: 35%; accuracy of the detecting angle: 0.002.

[0033] Differential scanning for different crystalline forms of YC-6, which were obtained by the examples, were performed using STA409PC thermal analyzer (Netzsch, Germany), under the following settings: crucible: alumina crucible; carrier gas: N.sub.2; temperature: 20400 C., 10.0 K/min, 400 C. maintained by 10 min.

[0034] Analysis Parameters of the Single Crystal Diffraction, Powder Diffraction and DSC for the Four Crystalline Forms of YC-6

[0035] (1) The crystal structure information of crystalline form A of YC-6 obtained by X-ray single crystal diffraction is: the crystalline form belongs to the monoclinic crystal system and space group P2.sub.1, with lattice parameters of a=17.760.08 , b=7.300.08 , c=22.050.08 , =90.0, =103.23 0.5, =90.0, V=2775.36(5) .sup.3.

[0036] The crystalline form A of YC-6 showed diffraction peaks at diffraction angle 2 values of 4.40.1, 8.70.1, 9.30.1, 12.60.1, 13.00.1, 15.00.1, 15.60.1, 16.60.1, 17.30.1, 18.50.1, 19.60.1, 21.00.1, 21.80.1, 24.30.1, 27.90.1 degrees, with the X-ray powder diffraction diagrams showed in FIG. 2.

[0037] The differential scanning calorimetry (DSC) diagrams of crystalline form A of YC-6 is showed in FIG. 3, with the endothermic transition temperature of 2252 C.

[0038] (2) The crystal structure information of crystalline form B of YC-6 obtained by X-ray single crystal diffraction is: the crystalline form belongs to the monoclinic crystal system and space group P2.sub.1, with lattice parameters of a=11.270.08, b=7.400.08 , c=20.450.08 , =90.0, =94.940.5, =90.0, V=1699.24(3) .sup.3.

[0039] The crystalline form B of YC-6 showed diffraction peaks at diffraction angle 2 values of 4.30.1, 8.60.1, 12.90.1, 17.20.1, 21.60.1 degrees, with the X-ray powder diffraction diagrams showed in FIG. 5.

[0040] The differential scanning calorimetry (DSC) diagrams of crystalline form B of YC-6 is showed in FIG. 6, with the endothermic transition temperature of 2232 C.

[0041] (3) The crystal structure information of crystalline form C of YC-6 obtained by X-ray single crystal diffraction is: the crystalline form belongs to the monoclinic crystal system and space group P2.sub.1, with lattice parameters of a=17.140.08 , b=6.400.08 , c=34.890.08 , =90.0, =91.05 +0.5, =90.0, V=3827.48(9) .sup.3.

[0042] The crystalline form C of YC-6 showed diffraction peaks at diffraction angle 2 values of 4.20.1, 8.50.1, 9.00.1, 12.50.1, 14.80.1, 15.40.1, 16.40.1, 16.80.2, 17.10.1, 18.30.1, 19.40.1, 20.80.1, 21.80.1, 24.10.1 degrees, with the X-ray powder diffraction diagrams showed in FIG. 8.

[0043] The differential scanning calorimetry (DSC) diagrams of crystalline form C of YC-6 is showed in FIG. 9, with the endothermic transition temperature of 2062 C.

[0044] (4) The crystal structure information of crystalline form D of YC-6 obtained by X-ray single crystal diffraction is: the crystalline form belongs to the orthorhombic crystal system and space group P2.sub.12.sub.12.sub.1, with lattice parameters of a=6.280.08 , b=12.560.08 , c=26.680.08 , =90.0, =90.0, =90.0, V=2103.09(7) .sup.3.

[0045] The crystalline form D of YC-6 showed diffraction peaks at diffraction angle 2 values of 4.00.1, 8.10.1, 8.50.1, 9.40.1, 12.50.1, 14.00.1, 14.90.1, 15.50.1, 16.40.1, 17.10.1, 18.30.1, 19.50.1, 20.50.1, 20.90.1, 21.50.1 degrees, with the X-ray powder diffraction diagrams showed in FIG. 11.

[0046] The differential scanning calorimetry (DSC) diagrams of crystalline form D of YC-6 is showed in FIG. 12, with the endothermic transition temperature of 2262 C.

EXAMPLE 1

[0047] Preparation of crystalline form A of YC-6:0.5 gof YC-6 was dissolved in 8 mL of acetone (5060 C.), which was added by the same amount of acetone to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 60 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 2

[0048] Preparation of crystalline form A of YC-6:0.5 gof YC-6 was dissolved in 10 mL of acetone at room temperature, which was added by the same amount of acetone to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 60 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 3

[0049] Preparation of crystalline form A of YC-6:0.5 gof YC-6 was dissolved in 7 mL of ethanol at room temperature, which was added by the same amount of ethanol to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 60 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 4

[0050] Preparation of crystalline form A of YC-6:0.5 gof YC-6 was dissolved in 12 mL of acetone at room temperature, which was added by water (a half amount of that of the acetone) to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 60 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 5

[0051] Preparation of crystalline form A of YC-6:0.5 gof YC-6 was dissolved in 10 mL of ethanol at room temperature, which was added by water (a half amount of that of the ethanol) to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 60 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

[0052] The tests showed that the crystals obtained in examples 1-5 share the same lattice parameters in X-ray single crystal diffraction, and that the crystals obtained thereby are all crystalline form A of YC-6.

EXAMPLE 6

[0053] Preparation of crystalline form B of YC-6:0.5 gof YC-6 was dissolved in 30 mL of ethyl acetate, which was then heated to 7080 C. After that, the solution was added by 30 mL of ethyl acetate to dilute, and then cooled and allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 7

[0054] Preparation of crystalline form B of YC-6:0.5 gof YC-6 was dissolved in 30 mL of ethyl acetate, which was then heated to 7080 C. After that, the solution was added by 30 mL of hexamethylene to dilute, and then cooled and allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 8

[0055] Preparation of crystalline form B of YC-6:0.5 gof YC-6 was dissolved in 8 mL of acetone, which was then heated to 50 C. After that, the solution was added by 24 mL of water to dilute, and then cooled and allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 9

[0056] Preparation of crystalline form B of YC-6:0.5 gof YC-6 was dissolved in 12 mL of acetone, which was then heated to 5060 C. After that, the solution was added by 36 mL of hexamethylene to dilute, and then cooled and allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

[0057] The tests showed that the crystals obtained in examples 69 share the same lattice parameters in X-ray single crystal diffraction, and that the crystals obtained thereby are all crystalline form B of YC-6.

EXAMPLE 10

[0058] Preparation of crystalline form C of YC-6:0.5 gof YC-6 was dissolved in 12 mL of ethanol at room temperature, which was added by the same amount of ethanol to dilute, and then allowed to form a crystalline precipitate at 10 C. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 11

[0059] Preparation of crystalline form C of YC-6:0.5 gof YC-6 was dissolved in 15 mL of ethanol at room temperature, which was added by the same amount of ethanol to dilute, and then allowed to form a crystalline precipitate at 10 C. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 12

[0060] Preparation of crystalline form C of YC-6:0.5 gof YC-6 was dissolved in 15 mL of ethanol at room temperature, which was added by twice amount of ethanol to dilute, and then allowed to form a crystalline precipitate at 10 C. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

[0061] The tests showed that the crystals obtained in examples 1012 share the same lattice parameters in X-ray single crystal diffraction, and that the crystals obtained thereby are all crystalline form C of YC-6.

EXAMPLE 13

[0062] Preparation of crystalline form D of YC-6:0.5 gof YC-6 was dissolved in 10 mL of tetrahydrofuran at room temperature, which was added by the same amount of tetrahydrofuran to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 14

[0063] Preparation of crystalline form D of YC-6:0.5 gof YC-6 was dissolved in 10 mL of tetrahydrofuran at room temperature, which was added by twice amount of tetrahydrofuran to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

EXAMPLE 15

[0064] Preparation of crystalline form D of YC-6:0.5 gof YC-6 was dissolved in 15 mL of tetrahydrofuran at room temperature, which was added by the same amount of tetrahydrofuran to dilute, and then allowed to form a crystalline precipitate. The single crystal obtained thereby was directly subjected to X-ray single crystal diffraction. Then the crystal was filtrated by suction and was air-dried at 70 C. to a constant weight, which was subjected to X-ray powder diffraction and differential scanning calorimetry.

[0065] The tests showed that the crystals obtained in examples 1315 share the same lattice parameters in X-ray single crystal diffraction, and that the crystals obtained thereby are all crystalline form D of YC-6.

[0066] The above examples are merely provided for description of the present invention, and are not intended to limit the scope of the present invention. The objects of the present invention can be achieved by skilled persons in the art in accordance with the disclosure of the present invention and the parameter ranges involved.