WO2014139447A1

WO2014139447A1 - Crystal form a of (1s)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-d-glucose and preparation method and use thereof

Info

Publication number: WO2014139447A1
Application number: PCT/CN2014/073365
Authority: WO
Inventors: 赵桂龙; 刘冰妮; 谢亚非; 刘钰强; 魏群超; 刘鹏; 王玉丽; 吴疆; 徐为人; 汤立达; 邹美香
Original assignee: 天津药物研究院
Priority date: 2013-03-15
Filing date: 2014-03-13
Publication date: 2014-09-18
Also published as: CN104045615A; CN104045615B

Abstract

Provided in the present invention is a crystal form A of (1S)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose, characterized in that X-ray powder diffraction as shown by angle 2θ has diffraction peaks around 3.56, 5.42, 10.84, 13.58, 16.28, 17.00, 18.48, 19.74, 21.72, 22.52, 22.96, 28.32 and 29.58. Also provided are the preparation method of the crystal form A, the use thereof in the preparation of pharmaceutical compositions for treating diabetes, and pharmaceutical compositions containing this crystal form.

Description

Crystal form A of (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose and preparation method and application thereof

The present invention relates to a crystalline form of a phenyl C-glucoside derivative containing a deoxyglucose structure, in particular to a (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl group. a crystal form of -1,6-dideoxy-D-glucose, a preparation method and application of the crystal form, and a pharmaceutical composition containing the crystal form. Background technique

The present inventors have made (ls)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose (for convenience of description, hereinafter abbreviated as I -D1-6) An invention patent application was filed as an inhibitor of Na ⁺ -glucose cotransporter 2 (or sodium-dependent glucose cotransporter 2 , abbreviated as SGLT2 ). The compound can be used for the preparation of a pharmaceutical composition for treating diabetes, and its chemical structural formula is as follows:

During the course of the research, the inventors have found that the final step of the preparation of the above compound ID 1 -6 is carried out by evaporating the solvent from the solution to obtain a product in the form of a kind between white foam and white solid. Solid matter, and this state fluctuates between batches, it is difficult to maintain a constant appearance state, and it is not suitable for direct use as a drug substance. At the same time, since the compound tends to exhibit a certain foaming property, the difficulty of further purification is increased, and it is difficult to prepare a high-purity raw material drug. Summary of the invention

Accordingly, it is an object of the present invention to overcome the above-mentioned drawbacks and to provide a crystalline form of I-D1-6 which has a stable appearance state, which contributes to further improving the purity of I-D1-6 and is improved. The storage stability can be stably supplied to prepare a drug substance, and a preparation method and application of the crystal form, and a pharmaceutical composition containing the crystal form are also provided.

The present invention provides a (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D- Form A of glucose (I-Dl-6), X-ray powder diffraction (PXRD, Powder X-ray Diffraction) at 2 Θ angles at 3.56, 5.42, 10.84, 13.58, 16.28, 17.00, 18.48, 19.74, 21.72 There are diffraction peaks near 22.52, 22.96, 28.32, and 29.58.

According to the crystal form A of the present invention, the X-ray powder diffraction has a d-value of the interplanar spacing d of 24.80, 16.29, 8.15, 6.52, 5.44, 5.21, 4.80, 4.49, 4.09, 3.94, 3.87, 3.15, 3.02 A. There is a diffraction peak near the position. Preferably, the interplanar spacing d value and the 2Θ angle may have the following correspondence:

Form A according to the invention, wherein differential thermal analysis (DTA, Differential Thermal)

Analysis ) The spectrum can have an endothermic peak at 147 °C.

According to the crystal form A of the present invention, the X-ray powder diffraction pattern thereof is substantially as shown in Fig. 2.

The present invention also provides a process for the preparation of the above Form A, which comprises: (1S)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy -D-glucose is dissolved in the lower alcohol, and then the lower alcohol can be heated, or the lower alcohol itself is hot, water is slowly added, crystallized under stirring, and the crystals are collected by suction filtration, followed by drying to obtain crystal form 8.

The method according to the present invention, wherein the lower alcohol has a temperature of 40 to 60 ° C, preferably 50 ° C. Preferably, it is naturally cooled to room temperature with stirring and devitrified. The room temperature is, for example, 25 to 35 ° C, and may be 25 to 27 ° C, and preferably 25 ° C. More preferably, the lower alcohol is selected from the group consisting of methanol or ethanol.

According to the method of the present invention, wherein (1S)-l-[4-chloro-3-(4-ethoxybenzyl)benzene The mass-to-volume ratio (g/ml) of the -1,6-dideoxy-D-glucose to the lower alcohol is 2:5-8, preferably 2:6. Preferably, the mass to volume ratio of the (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose to water (g/ M) is 2:8~10, preferably 2:9.

Preferably, the drying operation is carried out using a vacuum oil pump, and the drying time is 4 to 8 hours, preferably 5 hours.

The invention also provides a pharmaceutical composition comprising an effective amount of Form A of the invention and one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient may be a matrix or excipient that maintains the pharmaceutical dosage form, optionally comprising a carrier, excipient, diluent, filler, binder, depending on the choice of the agent or composition used. , disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, coating materials, and the like. Excipients include, for example, microcrystalline cellulose, lactose, pregelatinized starch, starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, glucose, fructose, water, polyethylene glycol, propylene glycol, glycerin, A composition of one or more of a cyclodextrin, a cyclodextrin derivative. The filler includes a composition of one or more of, for example, lactose, sucrose, dextrin, starch, pregelatinized starch, mannitol, sorbitol, dibasic calcium phosphate, calcium sulfate, calcium carbonate, microcrystalline cellulose. The binder includes, for example, one of sucrose, starch, povidone, carboxymethylcellulose, hypromellose, hydroxypropylcellulose, methylcellulose, polyethylene glycol, medicinal ethanol, water or Several compositions. The disintegrant includes a composition of one or more of, for example, starch, cross-linked poly-microketone, croscarmellose sodium, low-substituted hydroxypropylcellulose, carboxymethylcellulose, effervescent disintegrant .

The pharmaceutical composition according to the present invention, wherein the pharmaceutical composition may be a solid oral preparation, a liquid oral preparation or an injection. Preferably, the solid oral preparation comprises a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule or a granule; the liquid oral preparation includes an oral solution; the injection includes a water injection needle, and a lyophilized injection Powder needle, large infusion or small infusion.

The invention further provides the use of Form A or Form A prepared according to the process of the invention for the preparation of a pharmaceutical composition for the treatment of diabetes. The present inventors have found that I-D1-6 has an inhibitory action on SGLT2 enzyme and can be used as an active ingredient for the preparation of a therapeutic drug for diabetes. Further, it was confirmed by in vitro inhibition of humanized SGLT2 and rat urine glucose excretion model that the crystalline form A of the present invention has a high SGLT2 enzyme inhibitory activity.

The invention further provides the use of Form A of the invention or Form A prepared according to the process of the invention for the preparation of an inhibitor of a Type 2 glucosamine co-transporter.

The present invention also provides Form A of the present invention or Form A prepared according to the method of the present invention, which is useful as a medicament for treating diabetes.

The invention also provides a crystalline form A of the invention or a crystal prepared according to the method of the invention Type A, which acts as an inhibitor of the type 2 nanoglucose co-transporter.

The invention also provides a method of treating diabetes comprising administering to a patient a therapeutically effective amount of Form A of the invention or Form A prepared according to the methods of the invention.

The present invention also provides a method of treating diabetes by inhibiting a type 2 glucosamine co-transporter comprising administering to a patient a therapeutically effective amount of Form A of the present invention or Form A prepared according to the method of the present invention.

Form A of I-D1-6 of the present invention is effective over a relatively wide dosage range. For example, the daily dose is about 1 mg ~ 200 mg / person, divided into one or several doses. The dosage of Form A of the I-D1-6 to which the present invention is actually applied can be determined by a doctor according to the relevant circumstances. These conditions include: the physical condition of the subject, the route of administration, age, weight, individual response to the drug, severity of symptoms, and the like.

Between foamed and normal solids obtained by direct evaporation of the solution, etc.

Compared with the I-D1-6 sample, the I-D1-6 crystal form A prepared by the present invention has good appearance stability between batches (a white solid, not a certain degree of foamy characteristics) and reproduction. Sex, and the purity is further improved. For example, the inventors have found through experimentation that the crystal form A is stable in appearance in the batch range of 20 batches, and is a normal white solid, and each batch is stable crystal by PXRD and DTA analysis. Type A. In addition, the purity of Form A by HPLC analysis was 99.60%~99.81%, which was significantly higher than the purity of I-D1-6 raw material by 99.20%.

Further, the crystal form A of the present invention also has good storage stability. For example, the inventors have experimentally verified that the crystal form A has no significant increase in impurities in the two-week stability test for light, heat, and water vapor, and thus has good storage stability.

Based on the above characteristics, the crystal form A of the present invention can be used as a stable supply source of the I - D 1 - 6 raw material drug, and is more suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

Fig. 1 shows a differential thermal analysis (DTA) spectrum of the crystal form A obtained in Example 1. Fig. 2 shows a PXRD pattern of the crystal form A obtained in Example 1. The best way to implement the invention

The invention is further illustrated by the following examples, which are to be construed as being in no way This section provides a general description of the materials used in the tests of the present invention and the test methods. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. It will be apparent to those skilled in the art that, in the context, the materials and methods of operation of the present invention are well known in the art unless otherwise specified.

The measurement conditions of the crystal form A of the present invention are as follows in combination with the following examples:

X-ray powder diffraction (PXRD) conditions:

Instrument: Japanese Science D/Max-2500 18kW

Diffractometer: polycrystalline powder diffractometer

Target: Cu-Κα radiation, λ = 1.5405 A , 2Θ = 3~50.

Tube pressure: 40KV

Tube flow: 100mA

Scanning speed: 8 ° C / min

Crystalline graphite monochromator

DS/SS = 1°

RS: 0.3mm differential thermal analysis (DTA) conditions:

Instrument: Japanese Science PTC-10A TG-DTA Analyzer

Heating rate: 10 ° C / min

Scanning temperature range: 0~300°C

Reference: A1 ₂ 0 ₃

Sample size: 5.8 mg of crystal form to be tested A High performance liquid chromatography (HPLC) conditions:

Column: C ₁₈ , 150 mm x 4.6 mm, 5um

Mobile phase: Methanol: Water: Acetic acid = 70: 30: 0.25

Wavelength: 230 nm

Flow rate: 0.8 ml/min

Injection volume: 10 uL

Column temperature: 35 °C

Instrument:

General Analysis L6 Liquid Chromatograph

曰立L-7250 Autosampler General Analysis LC Win Chromatography Workstation Example 1

This example is intended to illustrate the crystal form A of the present invention I - D 1 - 6 and its preparation process.

I-D1-6 was prepared as a raw material. Can refer to the following reaction process:

Bu D1-6 The specific preparation process can be:

40.9 g (100 mmol) of the above compound 1 was dissolved in 300 mL of dry DMF, stirred under ice cooling, and 27.2 g (400 mmol) of imidazole was added, and then 16.6 g (110 mmol) was slowly added dropwise over 15 minutes. ) TBDMSCl (tert-butyldimethylsilyl chloride). After the addition was completed, the reaction mixture was further stirred at room temperature for 3 hours. The reaction mixture was diluted with 1500 mL of dichloromethane, washed with 500 mL of MgSO 3 brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated on a rotary evaporator. The obtained residue was subjected to silica gel column chromatography to afford purified product 2 as a white foam solid.

41.9 g (80 mmol) of compound 2 was dissolved in 300 mL of pyridine, and stirred under ice cooling. 150 mL of acetic anhydride was slowly added dropwise, followed by lg DMAP (4-dimethylaminopyridine). After the addition was completed, the reaction mixture was further stirred at room temperature overnight. The reaction mixture was poured into 2000 mL of ice water, stirred, and extracted with 500 mL x 3 dichloromethane. The organic phases were combined, washed successively with 500 mL of 5% diluted hydrochloric acid and 1000 mL of brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated to dryness eluted elution elution C. 39.0 g (60 mmol) of Compound 3 was dissolved in 500 mL of a 90% aqueous acetic acid solution, stirred at 45 ° C for 5 hours, then poured into 2000 mL of ice water and adjusted to pH = 7-8 with a saturated NaHCO ₃ solution. Extract with 500 mL x 3 dichloromethane. The organic phases were combined, washed with aq. The desiccant was removed by filtration, and the solvent was evaporated to dryness elution elution

126.9 g (500 mmol) of iodine was dissolved in 500 mL of dry methylene chloride. The ice water was stirred under cooling, and 131.1 g (500 mmol) of triphenylphosphine was slowly added. After the addition, the reaction mixture was stirred for 10 minutes. . Further, 136.2 g (2 mol) of imidazole was slowly added, and stirring was continued for one hour after the addition. To the above obtained system, 26.7 g (50 mmol) of Compound 5 was added, and after the addition, the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with 2000 mL of dichloromethane, washed with brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated on a rotary evaporator. The residue obtained was purified by silica gel column chromatography to afford purified product 5 as a white solid.

19.3 g (30 mmol) of compound 5, 29.1 g (100 mmol) of «-Bu ₃ SnH and 4.9 g (30 mmol) of AIBN were dissolved in 200 mL of dry benzene, and the mixture was refluxed under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled, diluted with 100 mL of dichloromethane, washed with brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent was evaporated on a rotary evaporator.

100 mL of dry anhydrous methanol was added to 0.5 g of metal nanoparticle, and stirred under a nitrogen atmosphere at room temperature until the metal nanoparticle disappeared. Then, 5.2 g (10 mmol) of compound 6 was added, and stirring was continued for 3 hours at room temperature. 5 g of strongly acidic cation exchange resin was added to the reaction system and stirred at room temperature overnight until the reaction mixture pH = 7. The resin was removed by suction filtration, and the filtrate was evaporated to dryness on a rotary evaporator, and the residue was further dried on a vacuum oil to afford product I-D 1-6 as a white foamy solid.

2.00 g of the product obtained by the above method I-D1-6 was placed in a 50 mL round bottom flask, 6 mL of absolute ethanol was added, stirred, and heated with hot water at 50 ° C to obtain a clear solution. Anhydrous ethanol can also be heated to 50 ° C and then added to a round bottom flask to dissolve the I-D 1-6. Then, 9 mL of water was slowly added dropwise to the round bottom flask. After the dropwise addition was completed, the heating source (e.g., hot water) was removed, and the mixture was stirred under natural cooling overnight to obtain a white crystal slurry system. The crystals were collected by suction filtration and placed on a vacuum oil pump 30. Drying at C for 5 hours gave 1.36 g of a white solid of the present invention I-D1-6.

68%.

The differential thermal analysis (DTA) pattern and the X-ray diffraction (PXRD) pattern of the I-D1-6 crystal form A are shown in Fig. 1 and Fig. 2, respectively, and the I-D1-6 crystal obtained in the present example can be determined. The type is crystal form A. Example 2

This example is intended to illustrate the crystal form A of the present invention I-D1-6 and its preparation process.

Compound I-D1-6 was prepared as a starting material in the same manner as in Example 1. 2.00 g of the product I-D1-6 obtained above was placed in a 50 mL round bottom flask, 5 mL of absolute ethanol was added, stirred, and heated with hot water at 40 ° C to obtain a clear solution. Anhydrous ethanol can also be heated to 40 ° C and then added to a round bottom flask to dissolve the I-D 1-6. Then, 8 mL of water was slowly added dropwise to the round bottom flask. After the addition was completed, the heating source (such as hot water) was removed, and the mixture was stirred under natural cooling overnight to obtain a white crystal slurry system. The crystals were collected by suction filtration and placed on a vacuum oil pump 30. Drying for 4 hours at C gave 1.20 g of the white solid I-D1-6 of the present invention, and the recovery was 60%.

The white solid was determined to be Form A of I-D1-6 by DTA and PXRD. Its DTA spectrum has an absorption peak around 147 °C. Example 3

Compound I-D1-6 was prepared as a starting material in the same manner as in Example 1.

2.00 g of the above-prepared product I-D1-6 was placed in a 50 mL round bottom flask, 8 mL of anhydrous ethanol was added, stirred, and heated with hot water at 60 ° C to obtain a clear solution. It is also possible to heat the anhydrous ethanol to 60 ° C and then add it to a round bottom flask to dissolve the I-D 1-6. Then, 10 mL of water was slowly added dropwise to the round bottom flask. After the addition was completed, the heating source (e.g., hot water) was removed, and the mixture was stirred overnight under cooling to obtain a white crystal slurry. The crystals were collected by suction filtration and placed on a vacuum oil pump 30. Drying for 8 hours at C gave 1.30 g of the white solid I-D1-6 of the present invention, and the recovery was 65%.

The white solid was determined to be Form A of I-D1-6 by DTA and PXRD. Its DTA spectrum has an absorption peak around 147 °C. Example 4

This example is intended to illustrate the preparation of a tablet containing Form I-D 1 -6 Form A of the present invention,

Prescription dosage / film

Example 1 Prepared sample 5 mg

:crystalline fiber: 80 mg

70 mg

Polyvinylpyrrolidone 6 mg

Carboxymethyl starch sodium salt 5 mg

Magnesium stearate 2 mg

Talc powder 2 mg

The sample prepared in Example 1 was in the form of a crystal form.

Mix thoroughly, add a solution containing the prescribed amount of poly(ethylene b:pyrrolidone), mix, make soft material, sieve, wet the granules, dry at 50~60 °C; then carboxymethyl starch, salt, hard Magnesium sulphate and slippery The stone powder was previously sieved, added to the above dried granules in a prescribed amount, and tableted to obtain a tablet containing I-D1-6 Form A. Test example 1

The crystal form A of I-D1-6 prepared in Example 1 was measured according to the method described in the literature (Meng, W. et al, J. Med. Chem., 2008, 51, 1 145-1 149) for SGLT2 and SGLT1. Inhibition of IC ₅ . value. The measurement results are shown in Table 1 below:

IC ₅₀ value of Form A of I-D1-6 for inhibition of SGLT2 and SGLT1

According to IC _{5 in the} above table. As a result of the measurement of the value, the crystal form A of I-D1-6 was a strongly selective SGLT2 inhibitor. Test example 2

The purity of Form A obtained in Example 1 was determined by HPLC to have a purity of 99.62%, and there were three small impurity peaks (0.21%, 0.04%, and 0.13%, respectively). The purity of the I-D1-6 material used to prepare the crystal form A was 99.1%, and there were 7 small impurity peaks (the corresponding impurities in the crystal form A were 0.32%, 0.08%, and 0.19%, respectively. There are 4 excess impurities 0.1 1%, 0.10%, 0.03% and 0.06%). It can be seen that the purity of the crystal form A is remarkably improved, and it is more suitable for mass production of pharmaceuticals. Test example 3

The influencing factors of the I-D1-6 crystal form A prepared in Example 1 and the comparative I-D1-6 raw material were tested under illumination (natural sunlight, average about 80,000 Lx), high temperature (60 ° C). It was placed under high humidity (100% relative humidity at 30 ° C) for two weeks (14 days), and the appearance, the number of impurities, and the amount of impurities (measured by HPLC) were compared with day 0. The test results are shown in Tables 2 to 4, respectively. Table 2 Light stability test data

Table 3 High temperature stability test data

Table 4 High humidity stability test data

As can be seen from Tables 2 to 4, in the stability test under the conditions of two weeks of illumination, high temperature and high humidity, the appearance of the crystal form A of the present invention showed no visible change, the crystal form remained stable, and was determined by HPLC. The number of impurities and the total amount of impurities are also not significantly increased, so that crystal form A has better storage stability than I-D1-6 raw material, and can be used as a stable source of I-D1-6 bulk drug. Test Example 4

The inhibitory ability of I-D1-6 Form A to SGLT2 was determined by a rat urine glucose excretion model.

After one month of high-fat and high-sugar feeding in normal SD rats, a small dose of streptavidin was injected intraperitoneally (model type 2 diabetes) to determine the blood glucose level before and after modeling. After successful modeling, the rats were randomly divided into groups (8/group) according to 24-hour urine sugar and body weight, respectively, a group of blanks (administer an equal volume of 0.5% CMC nanosolution) and a test compound group (6 mg). /kg ). Each group of rats was fasted for 16 hours before the experiment. After the rats were administered with I-D1-6 crystal form A prepared in Example 1 for 0.5 h by gavage, glucose (2 g/kg) was administered by intragastric administration. Urine was collected from 0 to 12 h after administration, and the urine sugar value was measured by glucose oxidase method at each time period. It was found in the experiment that Form A can induce 833 mg of urine sugar/200 g of body weight in this experiment, indicating that Form A has a strong ability to excrete urine sugar. While the invention has been described in detail, it is obvious that various changes in the various conditions can be made without departing from the spirit and scope of the invention. It is to be understood that the invention is not limited to the embodiments, but is intended to be included within the scope of the appended claims.

Claims

1. A crystal form A of (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-D-glucose, characterized by: X-ray powder diffraction expressed at 2Θ angle has diffraction peaks near 3.56, 5.42, 10.84, 13.58, 16.28, 17.00, 18.48, 19.74, 21.72, 22.52, 22.96, 28.32, and 29.58.

2. The crystal form A according to claim 1, characterized in that its X-ray powder diffraction value at the interplanar spacing d is 24.80, 16.29, 8.15, 6.52, 5.44, 5.21, 4.80, 4.49, 4.09, 3.94, There are diffraction peaks near the positions of 3.87, 3.15, and 3.02 A; Preferably, there is the following correspondence between the interplanar spacing d value and the 2Θ angle:

3. The crystal form A according to claim 1 or 2, characterized in that its differential thermal analysis spectrum has an endothermic peak at 147°C.

4. The crystal form A according to any one of claims 1 to 3, characterized in that its X-ray powder diffraction pattern is as shown in Figure 2.

5. Preparation of (1S)-1-[4-chloro-3-(4-ethoxybenzyl) described in any one of claims 1 to 4 phenyl]-1,6-dideoxy-D-glucose crystal form A method, characterized in that the method includes: (lS)-l-[4-chloro-3-(4-ethoxybenzyl) [base]phenyl]-1,6-dideoxy-D-glucose was dissolved in lower alcohol, water was slowly added, crystallized under stirring, the crystals were collected by suction filtration, and then dried to obtain the crystal form.

6. The method according to claim 5, characterized in that the temperature of the lower alcohol is

40-60°C, preferably 50°C; preferably, it is naturally cooled to room temperature with stirring and crystallized; more preferably, the lower alcohol is selected from methanol or ethanol.

7. The method according to claim 5 or 6, characterized in that (ls)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-di The mass/volume ratio of deoxy-D-glucose to lower alcohol is

2:5-8, preferably 2:6; Preferably, the (lS)-l-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy- The mass-volume ratio of D-glucose to water is 2:8~10, preferably 2:9.

8. A pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective amount of the crystal form A described in any one of claims 1 to 4 and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8, characterized in that the pharmaceutical composition is a solid oral preparation, a liquid oral preparation or an injection; preferably, the solid oral preparation includes dispersible tablets, enteric-coated tablets, chewable tablets tablets, orally disintegrating tablets, capsules or granules; the liquid oral preparations include oral solutions; the injections include water for injection, freeze-dried powder for injection, large infusion or small

10. Use of the crystalline form A according to any one of claims 1 to 4 or the crystalline form A prepared according to the method according to any one of claims 5 to 7 in the preparation of a pharmaceutical composition for the treatment of diabetes. .

1 1. Crystalline Form A according to any one of claims 1 to 4 or crystalline Form A prepared according to the method according to any one of claims 5 to 7 in the preparation of inhibitors of type 2 sodium glucose cotransporter uses in.

12. The crystal form A according to any one of claims 1 to 4 or the crystal form A prepared according to the method of any one of claims 5 to 7, which is used as a medicine for treating diabetes.

13. The crystal form A according to any one of claims 1 to 4 or the crystal form A prepared according to the method according to any one of claims 5 to 7, which is used as an inhibitor of type 2 sodium glucose cotransporter. agent.

14. A method for treating diabetes, the method comprising adding a therapeutically effective amount of the crystal form A according to any one of claims 1 to 4 or the crystal form A prepared according to the method according to any one of claims 5 to 7. Type A is given to the patient.

15. A method for treating diabetes by inhibiting type 2 sodium glucose co-transporter, the method comprising adding a therapeutically effective amount of the crystal form A according to any one of claims 1 to 4 or according to claims 5 to 7 Crystalline Form A prepared by any of the methods is administered to the patient.