CN111559997A - A new crystal form of dapagliflozin and preparation method thereof - Google Patents

Abstract

The invention relates to a new crystal form of dapagliflozin and a preparation method thereof. Specifically, the X-ray powder diffraction pattern of the new crystal form of dapagliflozin of the present invention measured using Cu-Kα has characteristic diffraction peaks at the following 2θ angles: 5.347±0.2°, 7.623±0.2°, 10.484±0.2° , 15.308±0.2°, 15.850±0.2°. The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.

Description

A new crystal form of dapagliflozin and preparation method thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a new crystal form of dapagliflozin and a preparation method thereof.

Background technique

Dapagliflozin is a commonly used diabetes drug in clinical practice. Its mechanism of action is to inhibit sodium-glucose co-transporter 2 (SGLT2), which reabsorbs glucose from urine, thereby increasing urinary glucose excretion. Based on diet and exercise, dapagliflozin can be used as a monotherapy in patients with type 2 diabetes to improve glycemic control.

The original crystal form patent (CN20078024135.X) reported 10 co-crystals, including (S) propylene glycol monohydrate, (R) propylene glycol monohydrate, ethanolate, ethanol dihydrate, ethylene glycol dihydrate (A) ), ethylene glycol dihydrate (B), L-proline (1:2), L-proline (1:1), L-proline (1:1) hemihydrate compound, L-phenylalanine (1:1) compound. The original research did not obtain the non-crystalline form of dapagliflozin, but used propylene glycol monohydrate co-crystal, indicating that it is difficult to develop non-aqueous dapagliflozin crystal forms. Crystalline form of gliclazin.

A variety of dapagliflozin crystal forms are disclosed in the prior art. For example, Chinese patent CN106170482B discloses a crystal form of dapagliflozin, which is characterized at about 4.318 (20.45) in the X-ray powder diffraction pattern expressed by 2θ angle and interplanar spacing (d value). absorption peak. Chinese patent CN104829573B discloses a crystal form of dapagliflozin, and discloses the spectrum obtained by X-ray powder diffraction measurement using Cu-Kα rays.

However, these existing crystal forms have problems such as high water content, low purity, and poor product stability, and the preparation process has problems such as complicated operation, high cost, low yield, and large pollution. Therefore, there is a need for a new crystal form of dapagliflozin, which can overcome the above-mentioned shortcomings of the prior art.

SUMMARY OF THE INVENTION

The present invention provides a crystal form of dapagliflozin, the X-ray powder diffraction pattern measured using Cu-Kα has characteristic diffraction peaks at the following 2θ angles: 5.347±0.2°, 7.623±0.2°, 10.484±0.2°, 15.308±0.2°, 15.850±0.2°.

In one embodiment, the crystalline form has an X-ray powder diffraction pattern measured using Cu-Kα between six or more, seven or more, eight or more, nine or more, Ten or more, or eleven or more characteristic diffraction peaks at 2θ angles selected from the group consisting of: 5.347±0.2°, 7.623±0.2°, 8.143±0.2°, 9.446±0.2°, 10.484± 0.2°, 15.308±0.2°, 15.850±0.2°, 17.416±0.2°, 20.122±0.2°, 24.601±0.2°, 29.612±0.2°, 30.398±0.2°.

In another embodiment, the X-ray powder diffraction pattern of the crystal form measured using Cu-Kα is shown in FIG. 1 .

In another embodiment, the X-ray powder diffraction pattern analysis data of the crystal form measured using Cu-Kα is shown in Table 1.

Table 1. Analysis data of X-ray powder diffraction pattern measured using Cu-Kα of Dapagliflozin crystal form of the present invention

In another embodiment, the differential scanning calorimetry curve of the crystalline form has an endothermic peak at 53.89±3°C.

In another embodiment, the differential scanning calorimetry curve of the crystal form is shown in FIG. 2 .

In another embodiment, the thermogravimetric analysis curve of the crystalline form is about 0.943% weight loss at 150±3°C.

In another embodiment, the thermogravimetric analysis curve of the crystal form is shown in FIG. 3 .

In another embodiment, the present invention also discloses a method for preparing a crystal form of dapagliflozin, the method comprising: 1) dissolving amorphous dapagliflozin in water; 2) after filtering through a filter membrane, The filtrate is left to stand at low temperature for crystallization; and 3) suction filtration, and drying under reduced pressure.

The present invention also provides the application of the above dapagliflozin crystal form in the preparation of a medicament for the treatment of type 2 diabetes.

Description of drawings

Figure 1 shows the X-ray powder diffraction pattern of the dapagliflozin crystal form of the present invention.

Figure 2 shows the differential scanning calorimetry curve of the dapagliflozin crystal form of the present invention.

Figure 3 shows the thermogravimetric analysis curve of the dapagliflozin crystal form of the present invention.

Figure 4 shows the crystal habit of the dapagliflozin crystal form of the present invention.

Detailed ways

The present invention will be further described below with reference to the accompanying drawings and embodiments. However, it should be understood that these embodiments are only used to describe the present invention in more detail and should not be construed to limit the present invention in any form.

The reagents and methods used in the examples of the present invention are all conventional reagents and conventional methods in the art. It should be clear to those skilled in the art that, in the following, unless otherwise specified, the temperature is expressed in degrees Celsius (°C), and the operating temperature is carried out at room temperature, and the room temperature shown refers to 10°C to 30°C, preferably 20°C to 25°C; The allowable error of the melting point is ±1%; the yield is the mass percentage.

experimental method

1. X-ray powder diffraction (XRPD)

The XRPD data of the crystalline form was determined by Bruker (d8advance), and the diffraction parameters are as follows:

X-ray:

X-ray tube setting: 40kV, 25mA

Divergence slit: automatic

Monochromator: none

Scan Mode: Continuous

Scanning range (°2Theta): 4°-40°

Scanning speed (sec/step): 0.5

2. Differential scanning calorimeter (DSC)

The DSC data of the crystal form were determined by a TA (DSC 25) differential scanning calorimeter, and the thermal analysis parameters were as follows:

Temperature range (℃): 30-300

Scan rate (°C/min): 10

Shielding gas: nitrogen

3. Thermogravimetric analysis (TGA)

The TGA data of the crystal form were determined by a TA (TGA 550) instrument, and the thermal analysis parameters were as follows:

Temperature range (°C): 30-350°C

Scan rate (°C/min): 10

Shielding gas: nitrogen

5. High performance liquid chromatography (HPLC) detection

The conditions for HPLC detection are as follows:

technical effect

The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.

Example

The following examples are only used to illustrate the specific embodiments of the present invention, and are not intended to limit the present invention.

Example 1 Preparation of Dapagliflozin crystal form

Add 0.2 g of amorphous dapagliflozin (purchased from Shanghai Gaolanghua Co., Ltd., product number L01837-180301) into 30 ml of purified water and stir for 5 minutes, pass through a 0.45-micron filter membrane, transfer the filtrate into a beaker, seal with a sealing film, seal the small holes, and slowly Evaporate to dryness to obtain 0.15 g of rod-shaped crystals with a yield of 75% and a purity of 99.6%. The X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve of this crystal form were determined by the methods described above.

Example 2 Preparation of Dapagliflozin crystal form

Dissolve 0.5 g of amorphous dapagliflozin (purchased from Shanghai Gaolanghua Company, product number L01837-180301) in 300 ml of purified water, pass through a 0.45-micron filter membrane, and leave the filtrate at 0 to 10 °C for 24 to 36 hours to precipitate crystals. Suction filtration and drying under reduced pressure. 0.3 g was obtained, the yield was 60%, and the purity was 99.2%.

Example 3 Preparation of Dapagliflozin crystal form

Add 0.5g of amorphous dapagliflozin into a 25ml flask, dissolve it in 2ml of methanol, slowly add 12ml of purified water dropwise, add 10mg of seed crystals (the seed crystals are prepared by the method in Example 1), and keep it at 0 ~ 10 ℃ Set aside for 12h, filter with suction, and dry under reduced pressure at 20-30°C. 0.45 g was obtained, the yield was 90%, and the purity was 99.5%.

Example 4 Crystal habit

Through microscope observation, the crystal habit of the crystal form of Dapagliflozin prepared by the method in Example 1 of the present invention is rod-shaped (as shown in Figure 4), with good fluidity, which is beneficial to the dry tableting process of the preparation.

Example 5 Stability Experiment

The product in Example 1 was subjected to an accelerated test (test conditions: temperature: 30° C., humidity: 65%), and the change in purity before and after the acceleration was measured by HPLC. The results are shown in Table 2 below, indicating that after 30 days of treatment, the purity of the crystal form has no obvious change, and the crystal form is stable.

Table 2. Results of stability experiments

purity Impurity content 0 days 99.6% 0.2% 10 days 99.4% 0.6% 15 days 99.3% 0.7% 20 days 99.2% 0.8% 30 days 99.2% 0.8%

It should be understood that the above embodiments are only used to further illustrate the present invention, rather than limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art according to the above content of the present invention belong to the present invention. protected range.

Claims (9)

1. A crystal form of dapagliflozin having characteristic diffraction peaks at the following 2θ angles using an X-ray powder diffraction pattern measured by Cu-Kα: 5.347±0.2°, 7.623±0.2°, 10.484±0.2°, 15.308± 0.2°, 15.850±0.2°. 2. The crystal form of Dapagliflozin as claimed in claim 1, wherein the X-ray powder diffraction pattern measured using Cu-Kα is in six or more, seven or more, eight or more, Nine or more, ten or more, or eleven or more characteristic diffraction peaks at 2θ angles selected from the group consisting of: 5.347±0.2°, 7.623±0.2°, 8.143±0.2°, 9.446±0.2°, 10.484±0.2°, 15.308±0.2°, 15.850±0.2°, 17.416±0.2°, 20.122±0.2°, 24.601±0.2°, 29.612±0.2°, 30.398±0.2°. 3 . The crystal form of dapagliflozin according to claim 2 , which has an X-ray powder diffraction pattern measured using Cu-Kα as shown in FIG. 1 of the accompanying drawings. 4 . 4. The crystal form of dapagliflozin according to claim 1, wherein the differential scanning calorimetry curve has an endothermic peak at 53.89±3°C. 5. The crystal form of dapagliflozin according to claim 4, which has the differential scanning calorimetry curve shown in Figure 2 of the accompanying drawings. 6 . The crystal form of dapagliflozin according to claim 1 , wherein the thermogravimetric analysis curve has a weight loss of about 0.943% at 150±3° C. 7 . 7. The crystal form of dapagliflozin according to claim 6, which has the thermogravimetric analysis curve shown in Figure 3 of the accompanying drawings. 8. A method for preparing a crystal form of Dapagliflozin, the method comprising: 1) dissolving amorphous Dapagliflozin in water; 2) after filtration through a filter membrane, the filtrate is left to stand at low temperature for crystallization; and 3) Suction filtration and drying under reduced pressure. 9. The dapagliflozin crystal form of any one of claims 1-7 or the dapagliflozin crystal form prepared by the method of claim 8 in the preparation of a medicine for the treatment of type 2 diabetes application.

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