CRYSTAL FORM I OF CANAGLIFLOZIN AND PREPARATION METHOD THEREOF

Abstract

Disclosed in the present invention is a crystal form I of Canagliflozin, and an X-ray powder diffraction spectrum of the crystal form I has characteristic diffraction peaks when 2θ is at the position of 4.4±0.2°, 8.4±0.2°, 16.8±0.2°, 17.5±0.2°, 18.0±0.2°, and 22.8±0.2°. The crystal form is physically and chemically stable and is suitable for manufacturing of various preparations.

Claims

1. A crystal form I of Canagliflozin, having characteristic diffraction peaks at positions with 2θ values of 4.4±0.2°, 8.4±0.2°, 16.8±0.2°, 17.5±0.2°, 18.0±0.2°, and 22.8±0.2° in an X-ray powder diffraction pattern thereof.

2. The crystal form I of claim 1, further comprising characteristic diffraction peaks at positions with 2θ values of 12.1±0.2°, 12.6±0.2°, 15.3±0.2°, 19.3±0.2°, 20.4±0.2°, 22.2±0.2°, 23.0±0.2°, 24.6±0.2°, and 26.6±0.2° in the X-ray powder diffraction pattern thereof.

3. The crystal form I of claim 1, substantially having characteristic diffraction peaks as shown in FIG. 1 in the X-ray powder diffraction pattern thereof.

4. The crystal form I of claim 1, having an endothermic peak between 90° C. and 95° C. in a DSC scanning graph thereof.

5. A method for preparing the crystal form I of Canagliflozin of claim 1, comprising heating and dissolving Canagliflozin in a mixed solvent of a suitable good solvent and water, then adding water to precipitate Canagliflozin.

6. The method of claim 5, specifically comprising the following steps: 1) dissolving Canagliflozin with a mixed solvent of a suitable good solvent and water to obtain a Canagliflozin solution, wherein the dissolving temperature is 30˜100° C.; 2) reducing the temperature of the Canagliflozin solution to 20˜60° C., and adding water to precipitate Canagliflozin; 3) separating the precipitated solid by filtration or centrifugation; 4) optionally, drying the separated solid at atmospheric or reduced pressure conditions, wherein the drying temperature is 30˜80° C.

7. The method of claim 6, wherein the dissolving temperature in step 1) is 50˜80° C., the temperature in step 2) is 30˜50° C., and the drying temperature in step 4) is 40˜50° C.

8. The method of claim 5, wherein the suitable good solvent includes methanol, ethanol, isopropanol, acetone, tetrahydrofuran, N,N-dimethyl formamide, dimethyl sulfoxide, N,N-dimethyl acetamide, dioxane, or a mixture thereof.

9. The method of claim 8, wherein the suitable good solvent is methanol, ethanol, isopropanol or a mixture thereof.

10. The method of claim 5, wherein the volume ratio of the suitable good solvent to water is 1:1-3.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0046] FIG. 1 is an X-ray diffraction pattern of the crystal form I of Canagliflozin of the present invention.

[0047] FIG. 2 is a DSC-TGA graph of the crystal form I of Canagliflozin of the present invention.

[0048] FIG. 3 is an infrared spectrum of the crystal form I of Canagliflozin of the present invention.

DETAILED DESCRIPTION OF EMBODIMENTS

[0049] Hereinafter, the present invention will be further illustrated in conjunction with examples, which allow those skilled in the art to understand the substance of the present invention more completely and are not intended to limit the scope of the invention in any way.

[0050] The X-ray powder diffraction patterns as described in the present invention were collected on a Shimadzu XRD-6000 X-ray diffractometer, Japan. The parameters of the X-ray powder diffraction analysis of the present invention were as follows:

[0051] X-ray reflection parameter: CuKα

[0052] CuKα source (α=1.5406 Å)

[0053] Voltage: 40 kilovolts (KV)

[0054] Current: 30 milliamperes (mA)

[0055] Divergence slit: automatic

[0056] Scanning mode: continuous

[0057] Scanning range: 2˜45 degrees

[0058] Sampling width: 0.02 degree

[0059] Scanning speed: 2 degree/minute

[0060] The DSC-TGA graphs of the crystal form I of Canagliflozin of the present invention were collected on a Mettler 1100LF type instrument, Switzerland. The parameters of the DSC-TGA analysis of the present invention were as follows:

[0061] Temperature range: room temperature˜300° C.

[0062] Scanning rate: 10° C./min

[0063] Protection gas: Ar gas 50 ml/min

[0064] The IR spectra (KBr tablet) of the crystal form I of Canagliflozin of the present invention were collected on a Fourier Transform Infrared spectrometer (Nicolet Atavar FT-IR330) from US Nicolet company.

Example 1

[0065] 100 g Canagliflozin was dissolved in a mixed solvent of 300 ml methanol and 100 ml water at 50˜55° C., cooled to a temperature of 30˜35° C., and 200 ml water was added dropwise under stirring. After the completion of the addition, a mass of solid precipitated out and was filtered. The filter cake was dried under a reduced pressure at 700˜760 mmHg and 40˜50° C. to obtain 96 g Canagliflozin, HPLC: 99.89%. The test result for X-ray powder diffraction is shown in FIG. 1; the test result for DSC-TGA is shown in FIG. 2; and the test result for infrared spectrum is shown in FIG. 3.

Example 2 Preparation of Crystal Form I of Canagliflozin

[0066] 80 g Canagliflozin was dissolved in a mixed solvent of 350 ml ethanol and 150 ml water at 65˜70° C., cooled to a temperature of 35˜40° C., and 550 ml water was added dropwise under stirring. After the completion of the addition, a mass of solid precipitated out, cooled to room temperature, and filtered. The filter cake was dried under a reduced pressure at 650˜760 mmHg and 45˜50° C. to obtain 67 g Canagliflozin, HPLC: 99.88%. It was confirmed by X-ray powder diffraction analysis as crystal form I of Canagliflozin.

Example 3 Preparation of Crystal Form I of Canagliflozin

[0067] 100 g Canagliflozin was dissolved in a mixed solvent of 800 ml isopropanol and 300 ml water at 70˜80° C., cooled to a temperature of 40˜50° C., and 2100 ml water was added dropwise under stirring. After the completion of the addition, a mass of solid precipitated out, cooled to room temperature and filtered. The filter cake was dried under a reduced pressure at 680˜760 mmHg and 45˜50° C. to obtain 92 g Canagliflozin, HPLC: 99.92%. It was confirmed by X-ray powder diffraction analysis as a crystal form I of Canagliflozin.