WO2020151672A1 - Dapagliflozin crystal form, preparation therefor, and use thereof - Google Patents

Abstract

Provided are a new crystal form of dapagliflozin and a preparation method therefor, a pharmaceutical composition comprising the crystal form, and a use of the crystal form in preparation of a sodium-glucose cotransporter inhibitor and a pharmaceutical preparation for treating diabetes. Compared with the prior art, the provided dapagliflozin crystal form CSI has one or more improved properties, and is of great value to the optimization and development of this drug in the future.

Description

A kind of dapagliflozin crystal form and its preparation method and application Technical field

The invention relates to the field of medicinal chemistry. Specifically, it relates to the crystal form of dapagliflozin and its preparation method and use.

Background technique

Dapagliflozin (trade name: Farxiga) is a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. By inhibiting the expression of SGLT-2 in the kidney, it reduces the reabsorption of kidney glucose and increases urine The excretion of glucose in the liquid, thereby reducing the plasma glucose level. Dapagliflozin was jointly developed by AstraZeneca and Bristol-Myers Squibb. The drug was approved by the European Commission on November 12, 2012 for the treatment of adult type 2 diabetes. It is the world's first SGLT-2 inhibitor to be marketed.

The chemical name of dapagliflozin is: (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl) Tetrahydro-2H-pyran-3,4,5-triol, its structural formula is as follows:

Crystal form is a solid in which compound molecules are arranged in a three-dimensional order in the microstructure to form a crystal lattice. The phenomenon of drug polymorphism refers to the existence of two or more different crystal forms of the drug. Because of different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which in turn affects the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, the crystal form of a drug must be an important content of drug research and an important content of drug quality control.

WO2003099836A1 discloses dapagliflozin and its synthesis and purification methods to obtain an amorphous off-white dapagliflozin solid. This amorphous solid contains more organic solvent residues and cannot be used for drug development.

At the same time, because the molecules in the amorphous solid are arranged in disorder, they are in a thermodynamically unstable state. Amorphous solids are in a high-energy state and usually have poor stability. Amorphous drugs are prone to crystal transformation during the production and storage process, which makes the bioavailability and dissolution rate of the drug lose consistency, leading to changes in the clinical efficacy of the drug. In addition, the preparation of amorphous is usually a rapid kinetic solid precipitation process, which easily leads to excessive residual solvents, and its particle properties are difficult to control through the process, making it face great challenges in the practical application of drugs.

CN101479287B discloses several solid forms of dapagliflozin, including propylene glycol monohydrate, ethanol dihydrate, and co-crystals of dapagliflozin with proline, tryptophan or phenylalanine, but no mention is made A solid form of dapagliflozin that does not contain other organic components (such as organic alcohols or amino acids) other than dapagliflozin. Organic alcohol solvents are generally toxic to the human body, and the eutectic will have a certain impact on the ratio of raw and auxiliary materials and the compatibility of auxiliary materials. Therefore, there is a need in the art to obtain pure dapagliflozin in a solid form suitable for pharmaceutical preparation.

CN103958491B discloses the hydrate crystal form A and crystal form B of dapagliflozin, wherein the crystal form A is a dihydrate, the water content of the crystal form B cannot be determined, and the stability is worse than that of the crystal form A. In addition, CN106146446B discloses the crystal form C of dapagliflozin hemihydrate. Based on the disclosed method, the inventor of the present application has repeated experiments to obtain a white transparent gel, but crystal form C cannot be obtained.

Among all the solid forms of dapagliflozin disclosed in the prior art, the crystalline form A of dapagliflozin hydrate disclosed in CN103958491B is relatively stable and reproducible relative to other crystal forms, and does not contain organic solvents or co- Crystal ligands and other components are the most suitable solid form of dapagliflozin for pharmaceutical development. However, the inventor of the present application conducted repeated experiments and property tests on the crystalline form A of dapagliflozin hydrate disclosed in CN103958491B, and the results showed that the known dapagliflozin hydrate crystalline form A closed at 4°C. After being placed for 2 weeks under the conditions, part of the crystal is transformed into the crystalline form of the CSI of the present invention; after being placed for 2 weeks under 25°C/60%RH closed conditions, the crystallinity decreases, there is amorphism, and the powdery sample becomes a translucent solid. Therefore, there is still a need in the art to develop a pure crystalline form of dapagliflozin that is cheap, easy to prepare, and has good stability for the development of drugs containing dapagliflozin.

In order to overcome the shortcomings of the prior art, the inventor of the present application unexpectedly discovered that the crystalline form of dapagliflozin provided by the present invention has advantages in physical and chemical properties, preparation processing properties, and bioavailability, such as melting point and solubility There are advantages in at least one aspect of moisture absorption, purification, stability, adhesion, compressibility, fluidity, dissolution in and out of the body, and bioavailability, especially the solubility, moisture absorption, and stability. The drug development of dapagliflozin provides a new and better choice, which is of great significance.

Summary of the invention

The main purpose of the present invention is to provide a new crystal form of dapagliflozin and its preparation method and application.

According to the purpose of the present invention, the present invention provides a crystalline CSI of dapagliflozin (hereinafter referred to as "crystalline CSI").

On the one hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at the diffraction angle 2θ values of 6.3°±0.2°, 12.1°±0.2°, and 14.3±0.2°.

Further, the X-ray powder diffraction of the crystalline form CSI has characteristics at one, or two, or three of the diffraction angle 2θ values of 9.5°±0.2°, 18.1°±0.2°, 15.0°±0.2° Peaks; Preferably, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at three of the diffraction angles 2θ of 9.5°±0.2°, 18.1°±0.2°, and 15.0°±0.2°.

Further, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at one, or two, or three of the diffraction angle 2θ values of 18.9°±0.2°, 20.2°±0.2°, 22.3±0.2° Preferably, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at three of the diffraction angles 2θ of 18.9°±0.2°, 20.2°±0.2°, and 22.3±0.2°.

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form CSI has a diffraction angle 2θ value of 6.3°±0.2°, 12.1°±0.2°, 14.3±0.2°, 9.5°±0.2°, 18.1 °±0.2°、15.0°±0.2°、18.9°±0.2°、20.2°±0.2°、22.3±0.2°any 3 places, or 4 places, or 5 places, or 6 places, or 7 places, or There are characteristic peaks at 8 or 9 locations.

Without limitation, the X-ray powder diffraction pattern of the crystalline form CSI is basically as shown in FIG. 4.

In a non-limiting manner, the differential scanning calorimetry diagram of the crystal form CSI is basically as shown in FIG. 6, an endothermic peak begins to appear near 47° C., and the endothermic peak is a dehydration endothermic peak.

In a non-limiting manner, the thermogravimetric analysis chart of the crystalline form CSI is basically as shown in FIG. 5, and there is a mass loss of about 4.0% when heated to 53°C, and about 1.9% of mass loss when heated to 80°C.

Without limitation, the crystal form CSI is a hydrate.

According to the objective of the present invention, the present invention also provides a preparation method of the crystal form CSI, and the preparation method includes:

(1) Dissolve the dapagliflozin raw materials in an ester solvent, add the ester solvate to an alkane solvent or a mixed solvent of ether solvent and alkane at -20℃-10℃, suspend and stir to obtain the crystal form CSI ;or

(2) Dissolve dapagliflozin raw materials in ether solvents, add alkane solvents and 1-3 equivalents (relative to dapagliflozin) of water at -20℃-10℃, stir and precipitate solids to obtain crystal form CSI; or

(3) Step 1: Preparation of the seed bed: Suspend the crystal form CSI seed crystals in alkane to obtain a seed suspension, and add the seed suspension to the alkane and stir to form a seed bed;

Step 2: Preparation of dapagliflozin solution: Dissolve dapagliflozin solid in ether solvent and add a certain amount of water to form dapagliflozin solution;

Step 3: Preparation of crystalline CSI: slowly drop the dapagliflozin solution in step 2 into the seed bed, stir overnight, filter and dry to obtain crystalline CSI.

Further, in the method (1), the ester solvent is preferably ethyl acetate or isopropyl acetate, the alkane solvent is preferably n-heptane, and the ether solvent is preferably methyl tert-butyl ether;

Further, in the method (2), the ether solvent is preferably methyl tert-butyl ether, and the alkane solvent is preferably n-heptane;

Further, in the method (3), the alkane in step 1 is preferably methylcyclohexane, the temperature of the alkane in step 1 is preferably 0-10°C; the ethers in step 2 are preferably methyl tert-butyl ether, and the certain The amount of water is preferably 1.2-2.0 equivalents.

The crystal type CSI provided by the present invention has the following beneficial effects:

(1) Compared with the prior art, the crystal form CSI of the present invention has higher solubility. Especially in water, the solubility of crystal form CSI and prior art crystal form A are 1.6060 mg/mL and 1.3640 mg/mL, respectively; in SGF, the solubility of crystal form CSI and prior art crystal form A are 1.2343 mg/mL respectively. mL and 1.0657mg/mL. It can be seen that in water and SGF, the solubility of crystal form CSI is increased to 117.8% and 115.8%, respectively, compared with crystal form A in the prior art.

Higher solubility is conducive to improving the absorption of the drug in the human body, increasing the bioavailability, and enabling the drug to exert a better therapeutic effect; in addition, the higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug Side effects and improve the safety of drugs.

(2) Compared with the prior art, the crystal form CSI of the present invention has lower hygroscopicity. The test results show that the moisture absorption weight gain of crystal form CSI under 80%RH conditions is 0.21%, which is close to no or almost no moisture absorption. The prior art crystal form A has a moisture absorption weight gain of 1.05% under 80%RH conditions. Slightly hygroscopic.

The hygroscopicity directly affects the physical and chemical stability of the drug, and the high hygroscopicity can easily cause chemical degradation and crystal transformation. In addition, high hygroscopicity will reduce the fluidity of the drug, thereby affecting the processing technology of the drug. Moreover, drugs with high hygroscopicity need to maintain low humidity during the production and storage process, which puts forward higher requirements on production and requires high costs. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in the medicine, which affects the quality of the medicine. The low hygroscopicity crystal type is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.

(3) Compared with the prior art, the crystalline CSI provided by the present invention has better stability. The crystal form CSI is placed at 4° C. The crystal form has not changed for at least 2 months, and the chemical purity is above 99.96%, and the purity remains basically unchanged during storage. The crystal form A of the prior art is partially converted to crystal form CSI of the present invention after being placed at 4°C for 2 weeks.

At the same time, the crystal form of CSI has not changed after being placed at 25°C/60%RH for at least 2 months, and the chemical purity is above 99.96%, and the purity remains basically unchanged during storage. However, the crystallinity of the prior art crystal form A decreases after being placed under the condition of 25° C./60% RH, resulting in amorphism, and the powdery sample becomes a translucent solid. It shows that the crystalline CSI bulk drugs and preparations have good stability under long-term conditions, which is conducive to the storage of drugs.

In addition, the crystal form CSI can be stable for at least 1 month at 11.3%RH-57.6%RH at room temperature.

The transformation of the crystal form will cause changes in the absorption of the drug, affect the bioavailability, and even cause the toxic side effects of the drug. Good chemical stability can ensure that almost no impurities are generated during storage. Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and minimizing changes in drug quality, bioavailability, and even toxic side effects caused by changes in crystal form or impurities. .

(4) The crystal form CSI of the present invention has better in vitro dissolution rate and dissolution rate. The dissolution rate of the crystalline CSI preparation in 0.1N HCl medium reached 95.6% at 60 minutes. Different crystal forms may lead to different dissolution rates of the preparation in the body, directly affecting the absorption, distribution, metabolism, and excretion of the preparation in the body, and ultimately lead to differences in clinical efficacy due to different bioavailability. Dissolution rate and dissolution rate are important prerequisites for drug absorption. Good in vitro dissolution rate indicates that the drug has a higher degree of in vivo absorption and better exposure characteristics in vivo, thereby improving bioavailability and improving drug efficacy; high dissolution rate enables the drug to reach the highest concentration in plasma quickly after administration Value to ensure that the drug takes effect quickly.

According to the purpose of the present invention, the present invention also provides a pharmaceutical composition, the pharmaceutical composition comprising an effective therapeutic amount of crystalline CSI and a pharmaceutically acceptable carrier, diluent or adjuvant.

Further, the present invention provides the use of crystalline CSI in the preparation of sodium-glucose cotransporter inhibitor drugs.

Furthermore, the present invention provides the use of crystalline CSI in the preparation of medicines for treating diabetes.

In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, at a stirring speed of 50-1800 revolutions per minute, wherein the magnetic stirring is preferably 300-900 revolutions per minute, and mechanical stirring Preferably it is 100-300 revolutions per minute.

The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The operation of "centrifugation" is: place the sample to be separated in a centrifuge tube and centrifuge at a rate of 10,000 rpm until all solids sink to the bottom of the centrifuge tube.

The "drying" can be performed at room temperature or higher. The drying temperature is from room temperature to about 60°C, or to 50°C, or to 40°C. The drying time can be 2-48 hours, or overnight. Drying is carried out in a fume hood, blast oven or vacuum oven.

In the present invention, "crystal" or "polymorph" refers to a solid confirmed by X-ray powder diffraction characterization. Those skilled in the art can understand that the physical and chemical properties discussed here can be characterized, and the experimental error depends on the condition of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known by those skilled in the art that the X-ray powder diffraction pattern usually changes with the different instrument conditions. In particular, it should be pointed out that the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the order of the diffraction peak intensities cannot be the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal. The intensity of the diffraction peaks shown in this article are illustrative rather than for absolute comparison. In addition, the experimental error of the position of the diffraction peak is usually 5% or less, and the error of these positions should also be taken into consideration, and an error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as sample thickness, the overall angle of the diffraction peak will be shifted, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of a crystal form in the present invention does not have to be exactly the same as the X-ray powder diffraction pattern in the embodiment referred to here, and any characteristic peaks in these patterns. The crystal forms of the same or similar X-ray powder diffraction patterns fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.

In some embodiments, the crystalline form of CSI of the present invention is pure, and substantially no other crystal forms are mixed. In the present invention, "substantially no" when used to refer to a new crystal form means that this crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less. Other crystal forms that are less than 5% by weight, and even less than 1% by weight.

The term "about" in the present invention, when used to refer to a measurable value, such as the mass, time, temperature, etc. of the compound and preparation, means that there can be a certain range of fluctuation around the specific value, and the range can be ±10% , ±5%, ±1%, ±0.5%, or ±0.1%.

Description of the drawings

Figure 1 is an XRPD diagram of the crystal form CSI obtained according to Example 1

Figure 2 is an XRPD diagram of the crystal form CSI obtained according to Example 2

Figure 3 is an XRPD diagram of the crystal form CSI obtained according to Example 3

Figure 4 is an XRPD diagram of the crystal form CSI obtained according to Example 4

Figure 5 is a TGA diagram of the crystal form CSI obtained according to Example 4

Figure 6 is a DSC chart of the crystal form CSI obtained according to Example 4

Figure 7 is the XRPD comparison chart of the crystalline form of the CSI of the present invention before and after being placed closed at 4°C and 25°C/60% relative humidity for 2 months (from top to bottom: before placement, placed at 4°C closed for 2 months, at 25°C ℃/60% relative humidity closed for 2 months)

Figure 8 is a comparison of XRPD before and after the prior art crystal form A is placed in a closed mouth at 4°C for 2 months (from top to bottom: before placing, placed in a closed mouth at 4°C for 2 weeks, and crystal form CSI is used for comparison)

Figure 9 is a comparison of XRPD of prior art crystal form A before and after being placed in a closed position at 25°C/60% relative humidity for 2 weeks (from top to bottom: before placement, placed in a closed place at 25°C/60% relative humidity for 2 weeks)

Figure 10 is the XRPD comparison chart of crystalline CSI before and after being placed at 11.3%RH-57.6%RH at room temperature for 1 month (from top to bottom: before placement, at 11.3%RH, 22.5%RH, 32.8%RH , 43.2%RH and 57.6%RH exposure after 1 month)

Figure 11 is the XRPD diagram of crystalline CSI before and after the pharmacopoeial method for testing moisture absorption (from top to bottom: before test, after test)

Figure 12 is the dissolution profile of the crystalline CSI preparation of the present invention

detailed description

The present invention will be described in detail with the following examples, which describe in detail the preparation and use methods of the crystal form of the present invention. It is obvious to those skilled in the art that many changes to both the material and the method can be implemented without departing from the scope of the present invention.

The explanation of the abbreviations used in the present invention is as follows:

XRPD: X-ray powder diffraction

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

HPLC: high performance liquid chromatography

Instruments and methods used to collect data:

The X-ray powder diffraction patterns of Example 4 and Example 6 of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

X-ray light source: Cu, Kα

Kα1

1.54060; Kα2

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 30 thousand volts (kV)

Current: 10 milliampere (mA)

Scan range: from 3.0 to 40.0 degrees

The X-ray powder diffraction patterns of Examples 1-3 and Example 7 of the present invention were collected on a Bruker D8 Discover X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:

X-ray light source: Cu, Kα

Kα1

1.54056; Kα2

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 40 kilovolts (kV)

Current: 40 milliampere (mA)

Scan range: from 4.0 to 40.0 degrees

The differential scanning calorimetry (DSC) chart of the present invention was collected on TA Q2000. The method parameters of the DSC described in the present invention are as follows:

Scan rate: 10℃/min

Protective gas: nitrogen

The thermogravimetric analysis (TGA) chart of the present invention is collected on TA Q500. The method parameters of the TGA of the present invention are as follows:

Scan rate: 10℃/min

Protective gas: nitrogen

The HPLC method parameters of the dynamic solubility of the present invention are as follows:

The parameters of the HPLC method for substance detection in the present invention are as follows:

The UPLC method parameters for the dissolution of the formulations of the present invention are as follows:

Unless otherwise specified, the following examples are all operated at room temperature. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

According to the present invention, the dapagliflozin and/or its salt as a raw material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, dapagliflozin and/or its salt as a raw material is in solid form.

The dapagliflozin and/or its salt used in the following examples can be prepared according to the prior art, for example, according to the method described in the CN101628905B document.

detailed description

Examples 1 to 4: Preparation method of crystal form CSI

Example 1

Weigh about 20 mg of dapagliflozin raw material, stir in 1 mL of ethyl acetate and n-heptane (1:1, V/V) mixed solvent for 12 hours at -20°C, then separate dapagliflozin ethyl acetate solvent Compound seed.

Weigh about 5 g of dapagliflozin raw material, dissolve it in 50 mL of ethyl acetate, add the above seed crystals, and stir to precipitate a solid. After adding 50 mL of n-heptane, the solid further precipitated out. Under the condition of 0-10° C., the obtained solid was suspended and stirred in 60 mL of n-heptane for 4 days, and the solid was separated to obtain the crystal form CSI.

The XRPD diagram of the crystal form CSI obtained in this embodiment is shown in FIG. 1, and the XRPD data is shown in Table 1.

Table 1

Diffraction angle 2θ	d value	Relative Strength(%)
6.33	13.96	33.98
9.49	9.32	22.36
10.92	8.10	15.88
11.20	7.90	13.65
12.21	7.25	15.24
14.33	6.18	43.50
15.07	5.88	39.20
15.44	5.74	30.11
15.81	5.61	27.06
16.19	5.48	21.75
17.87	4.96	46.00
18.14	4.89	100.00
18.94	4.69	24.13
20.26	4.38	28.29
21.02	4.23	15.73
21.64	4.11	22.15
22.06	4.03	16.49
22.43	3.96	27.65
23.37	3.81	16.51
24.04	3.70	12.23
25.99	3.43	18.05
27.08	3.29	10.95

27.68	3.22	12.09
28.63	3.12	13.60
31.21	2.87	7.91
31.89	2.81	6.31
33.16	2.70	6.47
34.94	2.57	6.04

Example 2

Weigh about 103.0mg of dapagliflozin raw material, stir in 1.5mL isopropyl acetate/n-heptane (1:2, V/V) mixed solvent for 5 hours at room temperature to separate isopropyl acetate solvate Seed crystal.

Weigh about 5 g of dapagliflozin raw material and dissolve it in 50 mL of isopropyl acetate. Add 10 mL of n-heptane and the above seed crystals, and stir to precipitate a solid. Add 50mL n-heptane to further precipitate the solid. At 5°C, the obtained solid was suspended and stirred in a mixed solvent of 80 mL methyl tert-butyl ether/n-heptane (1:9, V/V) for 7 days, and then separated The solid obtained crystal form CSI.

The XRPD diagram of the crystal form CSI obtained in this embodiment is shown in FIG. 2, and the XRPD data is shown in Table 2.

Table 2

Diffraction angle 2θ	d value	Relative Strength(%)
6.33	13.96	46.87
9.45	9.36	25.41
10.86	8.15	17.19
12.12	7.31	14.54
14.21	6.23	53.94
15.01	5.90	43.24
15.44	5.74	55.26
15.89	5.58	38.71
18.10	4.90	100.00
18.82	4.72	35.83
20.13	4.41	41.53
21.09	4.21	42.61
21.89	4.06	55.68
22.34	3.98	50.05
23.12	3.85	42.86
24.00	3.71	43.87
24.75	3.60	33.26
25.67	3.47	41.83

26.93	3.31	29.16
27.62	3.23	30.58
28.61	3.12	33.77
29.40	3.04	16.13
31.25	2.86	12.62
33.30	2.69	8.39
34.86	2.57	10.41

Example 3

Weigh 1.0 g of dapagliflozin raw material and dissolve it in 10 mL of methyl tert-butyl ether. Add 90 mL of n-heptane at 5° C., stir to precipitate a solid, add 1 equivalent (relative to the dapagliflozin raw material) of water and continue stirring. Filter and blast dry for 2 hours to obtain crystal form CSI.

The XRPD diagram of the crystalline CSI obtained in this embodiment is shown in FIG. 3, and the XRPD data is shown in Table 3.

table 3

Diffraction angle 2θ	d value	strength%
6.33	13.96	28.97
7.68	11.52	2.11
9.47	9.34	14.49
10.80	8.20	15.04
11.17	7.92	28.54
12.14	7.29	25.74
12.98	6.82	8.70
14.20	6.24	75.12
15.03	5.89	71.18
15.45	5.74	40.75
15.99	5.54	36.15
17.66	5.02	60.36
18.02	4.92	100.00
18.79	4.72	35.50
20.15	4.41	36.95
20.99	4.23	31.56
21.51	4.13	45.53
22.29	3.99	57.04
23.24	3.83	38.42
24.07	3.70	35.60
25.94	3.43	30.03

26.93	3.31	20.83
27.76	3.21	24.88
28.63	3.12	19.32
29.44	3.03	8.04
31.11	2.87	3.98
34.89	2.57	8.89
38.72	2.33	6.35

Example 4

Suspend 730 mg of crystalline CSI seed crystals in 40 mL of methylcyclohexane, and ultrasonically obtain a seed crystal suspension. The seed crystal suspension was added to 280 mL of methylcyclohexane pre-cooled to 5° C., and stirred to form a seed crystal bed. At the same time, 10.02 g of dapagliflozin ethyl acetate solvate was dissolved in 70 mL of methyl tert-butyl ether, and 635 μL of water was added to form a dapagliflozin solution. Subsequently, the solution was added dropwise to the seed bed, stirred at 5°C overnight and then filtered, and the obtained filter cake was placed in a forced air drying oven to dry at room temperature for 3 hours to obtain a white solid. The XRPD detects that the sample is crystalline CSI, and its X-ray powder diffraction data is shown in Figure 4 and Table 4.

TGA is shown in Fig. 5, heating to 53°C has a weight loss of about 4.0%, and heating to 80°C has a weight loss of about 1.9%.

DSC is shown in Figure 6, which has an endothermic peak, which begins to appear around 47°C, and this endothermic peak is a dehydration endothermic peak.

Table 4

Diffraction angle 2θ	d value	strength%
3.22	27.40	100.00
6.33	13.96	43.46
9.49	9.32	23.90
10.92	8.10	14.16
11.28	7.85	17.33
12.22	7.24	20.65
12.64	7.00	5.01
13.06	6.78	3.72
14.34	6.18	51.37
15.12	5.86	48.07
15.52	5.71	28.77
15.87	5.58	26.91
16.20	5.47	23.21
17.90	4.96	50.17
18.21	4.87	96.36
19.02	4.67	29.64
20.26	4.38	30.33
21.15	4.20	21.33
21.71	4.09	37.01
21.99	4.04	14.99

22.47	3.96	51.29
23.45	3.79	24.03
23.77	3.74	26.05
24.11	3.69	18.73
24.40	3.65	15.82
24.81	3.59	13.04
25.44	3.50	16.11
26.14	3.41	27.19
27.16	3.28	16.48
27.88	3.20	19.56
28.72	3.11	15.27
29.50	3.03	4.40
30.55	2.93	4.06
31.33	2.86	8.89
32.07	2.79	4.57
33.31	2.69	5.36
35.06	2.56	8.09
36.55	2.46	3.85
38.92	2.31	4.80

Example 5 Dynamic solubility of crystal form CSI

Simulated gastrointestinal fluids such as SGF (simulated gastric juice) are biologically related media. Such media can better reflect the impact of the physiological environment of the gastrointestinal tract on drug release. The solubility tested in this type of media and the solubility in the human environment Closer.

Take an appropriate amount of the crystal form CSI of the present invention and the prior art crystal form A respectively and disperse them in 3.0 mL of SGF solution. After equilibrating for 1 hour and 2 hours, the concentration of the sample in the saturated solution (mg/mL) is tested by high performance liquid chromatography. ), the results are shown in Table 5.

table 5

The results show that the dynamic solubility of crystal form CSI in SGF solution is higher than that of crystal form A in the prior art.

Example 6 Equilibrium solubility of crystal form CSI

Take an appropriate amount of the crystal form CSI of the present invention and the prior art crystal form A respectively and disperse them in 3.0 mL of aqueous solution. After equilibrating for 24 hours, the concentration of the sample in the saturated solution (mg/mL) is tested by high performance liquid chromatography. The results are as follows Table 6 shows.

Table 6

The results show that the equilibrium solubility of crystal form CSI in aqueous solution is higher than that of prior art crystal form A.

Example 7 Stability of crystal form CSI

Weigh about 5 mg of the crystal form CSI prepared by the present invention, and place them in a closed position at 4° C., 25° C./60% RH, and use HPLC and XRPD to determine the purity and crystal form. The XRPD comparison chart is shown in FIG. 7.

Weigh about 5 mg of crystal form A in the prior art, and place them in a closed position at 4° C., 25° C./60% RH. HPLC and XRPD are used to determine the purity and crystal form. The XRPD comparison chart is shown in Figure 8 and Figure 9 respectively.

Table 7 shows the stability data of crystal form CSI and prior art crystal form A under different conditions.

Table 7

The results show that the crystalline CSI can be stable for at least 2 months under closed conditions of 4°C and 25°C/60%RH, and the sample has good properties. On the contrary, the prior art crystal form A was partially transformed into the crystal form CSI after being placed in a closed condition of 4°C for 2 weeks; the crystallinity decreased after being placed in a closed condition of 25°C/60%RH for 2 weeks. The shape is produced, and the powdered sample becomes a translucent solid. It can be seen that the stability of crystal form CSI is better than that of crystal form A in the prior art.

The crystal form CSI prepared by the present invention is weighed and placed in an open place at room temperature and different humidity conditions, and the crystal form is determined by XRPD. The results are shown in Table 8, and the XRPD comparison chart is shown in Figure 10. The results show that the crystalline CSI can be stable for at least one month at 11.3%RH-57.6%RH at room temperature.

Table 8

Example 8 Hygroscopicity of crystal form CSI

Take appropriate amount of crystal form CSI and prior art crystal form A to conduct moisture absorption test according to the pharmacopoeia method. The moisture absorption and weight gain are calculated according to the formula: (m3-m2)/(m2-m1)×100%. The test results are shown in Table 9. As shown, the XRPD images of the crystal form CSI before and after the moisture absorption test are shown in Fig. 11.

Table 9

Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2015 Edition General Principles 9103 Guidelines for Drug Hygroscopicity Tests, experimental conditions: 25℃±1℃, 80% relative humidity):

Deliquescence: absorb enough water to form a liquid

Extremely moisture-absorbing: moisture-absorbing weight gain is not less than 15.0%

Has moisture absorption: moisture absorption weight gain is less than 15.0% but not less than 2.0%

Slight moisture absorption: weight gain is less than 2.0% but not less than 0.2%

No or almost no moisture absorption: less than 0.2% weight gain

(The definition of hygroscopicity in the ninth edition of the European Pharmacopoeia 5.11 is consistent with the Chinese Pharmacopoeia)

Tested by the pharmacopoeia method, the crystalline form CSI has a moisture-absorbing weight gain of 0.21%, which is close to no or no moisture-absorbing property. The prior-art solid moisture-absorbing weight gain of 1.05% is slightly moisture-absorbing. Compared with the prior art crystal form A, The crystalline CSI has a low moisture absorption and weight gain. Therefore, the hygroscopicity of crystal form CSI is better than that of crystal form A in the prior art.

Example 9 Preparation of crystal form CSI

Mix the crystalline CSI and the auxiliary materials uniformly according to the tablet prescription dosage in Table 10. According to the steps described in Table 11, use the ENERPAC manual tablet press to make the corresponding tablets. When compressing tablets, select a 12*6mm die with a pressure of 4KN, compress into tablets and coat the obtained tablets.

Table 10

Table 11

Example 10 In vitro dissolution of crystal form CSI preparation

The in vitro dissolution of the crystalline CSI-containing tablets obtained in Example 9 was tested, and the dissolution was determined in accordance with the Chinese Pharmacopoeia 2015 Edition 0931 Dissolution and Release Determination Method, and the conditions are as follows:

Dissolution medium: 0.1N HCl

Dissolution method: paddle method

Medium volume: 900mL

Speed: 75rpm

Medium temperature: 37℃

The in vitro dissolution conditions of the crystalline CSI preparation are shown in Table 12 and Figure 12 below, indicating that the tablet with the crystalline CSI of the present invention as an active ingredient has good dissolution.

Table 12

Time (min)	Cumulative dissolution rate (%)
0	0.0
5	63.0
10	78.2
15	85.6
20	89.9
30	93.8
45	95.3
60	95.6

The above-mentioned embodiments are only to illustrate the technical concept and features of the present invention, and their purpose is to enable those familiar with the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered by the protection scope of the present invention.

Claims (7)

1. A crystalline form of dapagliflozin CSI, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has characteristics at 2θ values of 6.3°±0.2°, 12.1°±0.2°, 14.3°±0.2° peak.
2. The crystalline CSI according to claim 1, characterized in that Cu-Kα radiation is used, and its X-ray powder diffraction pattern has a 2θ value of 18.1°±0.2°, 9.5°±0.2°, 15.0°±0.2° There are characteristic peaks at 1 or 2 or 3 locations.
3. A preparation method of dapagliflozin crystal form CSI according to claim 1, wherein the method is:

   (1) Dissolve the dapagliflozin raw materials in an ester solvent, add the ester solvate to an alkane solvent or a mixed solvent of ether solvent and alkane at -20℃-10℃, suspend and stir to obtain the crystal form CSI ;or

   (2) Dissolve dapagliflozin raw materials in ether solvents, add alkane solvents and 1-3 equivalents (relative to dapagliflozin) of water at -20℃-10℃, stir and precipitate solids to obtain crystal form CSI; or

   (3) Step 1: Preparation of the seed bed: Suspend the crystal form CSI seed crystals in alkane to obtain a seed crystal suspension, and add the seed suspension to the alkane and stir to form a seed bed;

   Step 2: Preparation of dapagliflozin solution: Dissolve dapagliflozin solid in ether solvent and add a certain amount of water to form dapagliflozin solution;

   Step 3: Preparation of crystalline CSI: slowly drop the dapagliflozin solution in step 2 into the seed bed, stir overnight, filter and dry to obtain crystalline CSI.
4. The preparation method according to claim 3, in the method (1), the ester solvent is ethyl acetate or isopropyl acetate, the alkane solvent is n-heptane, and the ether solvent is methyl tert-butyl. Base ether; the ether solvent in method (2) is methyl tert-butyl ether, the alkane solvent is n-heptane; the alkane in step 1 in method (3) is methylcyclohexane, step 1 The temperature of the alkane is 0-10°C, and the ether in step 2 is methyl tert-butyl ether.
5. A pharmaceutical composition comprising an effective therapeutic amount of the crystalline CSI described in claim 1 and a pharmaceutically acceptable carrier, diluent or adjuvant.
6. Use of the crystalline form of CSI in claim 1 in the preparation of sodium-glucose cotransporter inhibitor drugs.
7. The use of the crystal form CSI described in claim 1 in the preparation of a medicine for treating diabetes.

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