Novel crystal form of bexagliflozin as well as preparation method and application thereof

Abstract

The invention relates to the technical field of chemical crystallization of medicines, and particularly discloses a novel crystal form of bexagliflozin as well as a preparation method and application of the novel crystal form. The invention discloses a novel crystal form of bexagliflozin. An X-ray powder diffraction pattern comprises characteristic diffraction peaks at a diffraction angle 2 theta, wherein the characteristic diffraction peaks are respectively 3.97 + / -0.2, 8.00 + / -0.2, 12.84 + / -0.2, 15.94 + / -0.2, 17.80 + / -0.2, 18.40 + / -0.2, 18.64 + / -0.2, 19.77 + / -0.2, 19.99 + / -0.2, 22.56 + / -0.2, 24.60 + / -0.2 and 25.32 + / -0.2; wherein the X-ray powder diffraction is generated by using a CuK alpha 1 ray. The bexagliflozin with the brand-new crystal form prepared by the invention is stable in chemical property, easy to store and relatively high in solubility in various solvents.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceutical chemical crystallization, specifically to a novel crystal form of besagliflozin and its preparation method and application. Background Technology

[0002] Bexagliflozin is an oral sodium-glucose cotransporter 2 (SGLT2) inhibitor that can be used to improve glucose control in adults with type 2 diabetes as an adjunct therapy in addition to diet and exercise.

[0003] As a diabetes treatment drug, besagliflozin has demonstrated excellent performance in lowering blood glucose levels in clinical trials. Compared with traditional hypoglycemic agents, it not only significantly reduces glycated hemoglobin (HbA1c) levels but also reduces weight and improves insulin sensitivity, making it an effective option for patients with type 2 diabetes, especially those who are obese.

[0004] The chemical name of besagliflozin is (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)benzene)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-ol, and it has the chemical structural formula shown in formula (1):

[0005] Equation (1).

[0006] A study reported a new crystal form of besagliflozin obtained by crystallizing the proline crystal form of besagliflozin in methanol and water. Its X-ray powder diffraction pattern shows characteristic diffraction peaks at 2θ angles of 5.4, 11.2, 11.3, 11.9, 12.9, 15.5, 16.3, 17.8, 19.1, 20.0, 20.6, 20.7, 21.2, 22.8, 23.0, 23.4, 23.6, 23.9, 24.7, 25.4, 25.8, 27.8, and 28.2. This crystal form can be obtained by precipitation from acetonitrile, ethanol, ethyl acetate, isopropanol, butanol, butanone, 1,4-dioxane and heptane (1:1), and isopropanol and ethyl acetate (1:1). However, the solubility of this crystal form was found to be poor. Summary of the Invention

[0007] To address the aforementioned technical problems, this application provides a novel crystal form of besagliflozin, its preparation method, and its application.

[0008] In a first aspect, this application provides a novel crystalline form of bexagliflozin, the X-ray powder diffraction pattern of which includes characteristic diffraction peaks at a diffraction angle of 2θ at 3.97±0.2, 8.00±0.2, 12.84±0.2, 15.94±0.2, 17.80±0.2, 18.40±0.2, 18.64±0.2, 19.77±0.2, 19.99±0.2, 22.56±0.2, 24.60±0.2, and 25.32±0.2; wherein the X-ray powder diffraction is generated using CuKα1 rays.

[0009] In the process of studying the crystal form of besagliflozin, this application prepared a novel crystal form that is chemically stable, easy to store, and has significantly increased solubility in various solvents.

[0010] Specifically, the X-ray powder diffraction pattern of the new crystal form of bexagliflozin has an intensity greater than 50% at a diffraction angle of 2θ.

[0011] Preferably, the X-ray powder diffraction pattern of the new crystal form of bexagliflozin contains characteristic diffraction peaks at a diffraction angle of 2θ at 3.97±0.2, 8.00±0.2, 12.84±0.2, 14.57±0.2, 15.94±0.2, 16.33±0.2, 17.80±0.2, 18.40±0.2, 18.64±0.2, 19.01±0.2, 19.77±0.2, 19.99±0.2, 21.33±0.2, 21.60±0.2, 22.56±0.2, 23.23±0.2, 23.62±0.2, 24.60±0.2, 25.32±0.2, 25.84±0.2, and 26.41±0.2.

[0012] Specifically, the X-ray powder diffraction pattern of the new crystal form of bexagliflozin has an intensity greater than 25% at a diffraction angle of 2θ.

[0013] Preferably, the melting point of the new crystal form of bexagliflozin is 50–70°C.

[0014] Preferably, the new crystal form of besagliflozin loses 2.0-2.5% of its weight at 100-105°C.

[0015] Secondly, this application provides a bexagliflozin with a novel crystal form, wherein the bexagliflozin has the aforementioned novel crystal form.

[0016] Thirdly, this application provides a method for preparing a new crystal form of bexagliflozin, specifically comprising the following steps in sequence: (1) Dissolve bexagliflozin in an organic solvent at a solid-liquid ratio of 1g:2-10mL, and cool to -20-10℃ to obtain a mixed solution; the organic solvent is composed of one or two of methanol and ethanol mixed with n-heptane; (2) Water is added dropwise to the mixed solution, and a white solid precipitates out; the volume ratio of water to organic solvent is 1:1.2 to 2.5; (3) Collect the white solid, wash it with water, and dry it under vacuum at 30-50℃ to obtain the product.

[0017] Preferably, in step (1), the solid-liquid ratio is 1g:3-8mL; the cooling temperature is -10 to 0℃; and the organic solvent is composed of methanol and n-heptane mixed in a volume ratio of 10:0.5-1.5.

[0018] In one specific implementation, in step (1), the solid-liquid ratio is 1g:2mL, 1g:3mL, 1g:5mL, 1g:8mL, 1g:10mL; the cooling temperature is -20~-15℃, -15~-10℃, -10~-5℃, -5~0℃, 0~5℃, 5~10℃; the organic solvent is composed of methanol and n-heptane mixed in volume ratios of 10:0.5, 10:1, and 10:1.5.

[0019] Preferably, in step (2), the volume ratio of water to organic solvent is 1:1.5 to 2.0; and the water is added dropwise over a period of 10 to 30 minutes.

[0020] In one specific implementation, in step (2), the volume ratio of water to organic solvent is 1:1.2, 1:1.5, 1:1.7, 1:2.0, or 1:2.5; and the water is added within 10 minutes, 20 minutes, or 30 minutes.

[0021] Preferably, in step (3), the vacuum drying temperature is 35-45°C and the time is 3-12 hours.

[0022] In one specific implementation, in step (3), the vacuum drying temperature is 30℃, 35℃, 40℃, 45℃, 50℃, and the time is 2h, 3h, 5h, 7h, 10h, 12h.

[0023] Fourthly, this application provides a pharmaceutical composition characterized by comprising the novel crystalline form or bexagliflozin having the novel crystalline form.

[0024] Fifthly, this application provides the use of the novel crystalline form or the besagliflozin having the novel crystalline form or the pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of type 2 diabetes.

[0025] The besagliflozin compound with a novel crystalline form provided in this application has activity as an inhibitor of sodium-dependent glucose transporters found in the intestines and kidneys of mammals.

[0026] Besaglitazone is a selective inhibitor of renal SGLT2 activity and can therefore be used to treat diseases or disorders related to SGLT2 activity.

[0027] The besagliflozin compounds with novel crystalline forms provided in this application can be administered to mammals, preferably humans, to treat a variety of symptoms and disorders, including but not limited to, treating or delaying diabetes (including type I and II, impaired glucose tolerance, insulin resistance, and diabetic complications such as nephropathy, retinopathy, neuropathy, and cataracts), hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated blood concentrations of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, and the progression or onset of hypertension. The compounds of this invention can also be used to increase the blood concentration of high-density lipoprotein (HDL).

[0028] In summary, the technical solution of this application has the following effects: This application discloses a novel method for preparing besagliflozin-based solid crystalline form. Compared with the prior art, the new crystal form of besagliflozin provided in this application has higher solubility, which is of great significance for improving efficacy and bioavailability. Furthermore, the new crystal form of besagliflozin has good stability under high temperature, high humidity, and light conditions, and can be used alone or in combination for the treatment of diseases or symptoms affected by SGLT or SGLT2 inhibition. Attached Figure Description

[0029] Figure 1 The X-ray powder diffraction pattern is the new crystal form of bexagliflozin in Example 1.

[0030] Figure 2 The differential scanning calorimetry (DSC) spectrum of the new crystal form of bexagliflozin in Example 1 is shown.

[0031] Figure 3 Thermogravimetric analysis (TGA) spectrum of the new crystal form of bexagliflozin in Example 1. Detailed Implementation

[0032] The present application will be further described in detail below with reference to embodiments, comparative examples and performance test results. These embodiments should not be construed as limiting the scope of protection claimed in this application.

[0033] The original crystal form of besagliflozin is derived from the crystal form patent of besagliflozin disclosed in WO2011 / 153953, which is obtained by crystallizing the proline crystal form of besagliflozin in methanol and water.

[0034] Unless otherwise specified, the experimental methods described in the following examples are conventional methods.

[0035] X-ray powder diffraction (XPRD) spectroscopy was performed using a Bruker D2 X-ray powder diffractometer. Differential scanning calorimetry (DSC) analysis was performed using a DSC Q2000 differential scanning calorimeter; thermogravimetric analysis (TGA) analysis was performed using a TGA Q50 thermogravimetric analyzer.

[0036] Example

[0037] Example 1

[0038] Example 1 provides a new crystal form of bexagliflozin and its preparation method.

[0039] The specific method for preparing the new crystal form of bexagliflozin in Example 1 is shown below.

[0040] (1) At room temperature, 20g of bexagliflozin was dissolved in 60mL of organic solvent at a solid-liquid ratio of 1g:3mL, and the solution was cooled to -10 to -5℃ to obtain a mixed solution; the organic solvent was composed of methanol and n-heptane mixed in a volume ratio of 10:1. (2) Within 20 min, add 120 mL of water to the mixed solution dropwise, and control the temperature within -10 to -2℃ during the dropwise addition. Stir vigorously for 1 h at a speed of 3000 rpm to precipitate a white solid; the volume ratio of water to organic solvent is 1:2. (3) Filter, collect the precipitated white solid, wash with water 3 times, and dry under vacuum at 40℃ for 5 hours to obtain the final product.

[0041] (4) Detection: such as Figure 1 The X-ray powder diffraction pattern of the new crystalline form of bexagliflozin in this embodiment is shown. Table 1 shows the relevant data of the 2θ angle of the X-ray powder diffraction of the new crystalline form of bexagliflozin in this embodiment; it can be seen that the 2θ angle includes positions at 3.97±0.2, 8.00±0.2, 12.84±0.2, 14.57±0.2, 15.94±0.2, 16.33±0.2, 17.80±0.2, 18.40±0.2, 18.64±0.2, and 19.0. Characteristic diffraction peaks of 1±0.2, 19.77±0.2, 19.99±0.2, 21.33±0.2, 21.60±0.2, 22.56±0.2, 23.23±0.2, 23.62±0.2, 24.60±0.2, 25.32±0.2, 25.84±0.2, and 26.41±0.2 (diffraction intensities below 25% are negligible).

[0042] Figure 2The figure shows the differential scanning calorimetry (DSC) spectrum of the new crystal form of besagliflozin in this embodiment; as can be seen from the figure, the melting point of the new crystal form of besagliflozin is 50-70℃.

[0043] Figure 3 The figure shows the thermogravimetric analysis spectrum of the new crystal form of besagliflozin in this embodiment; as can be seen from the figure, the new crystal form of besagliflozin loses about 2.0 to 2.5% of its weight at 100 to 105 °C.

[0044] Table 1. Relevant data on the diffraction angle 2θ of the new crystal form of bexagliflozin in Example 1 using X-ray powder diffraction.

[0045] Examples 2-6 Examples 2-6 respectively provide a new crystal form of bexagliflozin and its preparation method.

[0046] The difference between the above embodiments and Embodiment 1 is that the type of organic solvent or the cooling temperature in step (1) is different, as shown below.

[0047] In Example 2: The organic solvent is composed of ethanol and n-heptane mixed in a volume ratio of 10:1.

[0048] In Example 3: the organic solvent is composed of methanol, ethanol and n-heptane mixed in a volume ratio of 5:5:1.

[0049] In Example 4: the organic solvent was composed of methanol and n-heptane mixed in a volume ratio of 10:3.

[0050] In Example 5: the organic solvent was composed of methanol and n-heptane mixed in a volume ratio of 10:1.5.

[0051] In Example 6, the cooling temperature was 5–10°C.

[0052] All other process parameters in the above embodiments are the same as those in Embodiment 1.

[0053] Examples 7-8 Examples 7-8 respectively provide a new crystal form of bexagliflozin and its preparation method.

[0054] The difference between the above embodiment and embodiment 1 is that the vacuum drying temperature is different in step (3), as shown below.

[0055] In Example 7: the vacuum drying temperature was 30°C.

[0056] In Example 8: the vacuum drying temperature was 50°C.

[0057] All other process parameters in the above embodiments are the same as those in Embodiment 1.

[0058] Comparative Example Comparative Examples 1-3 Comparative Examples 1-3 provide a new crystal form of bexagliflozin and its preparation method, respectively.

[0059] The difference between the above comparative examples and Example 1 is as shown in Table 1.

[0060] In Comparative Example 1: the organic solvent is methanol.

[0061] In Comparative Example 2: the organic solvent was ethanol.

[0062] In Comparative Example 3, the cooling temperature was 12–17°C.

[0063] All other process parameters in the above comparative examples are the same as those in Example 1.

[0064] Performance testing (1) Solubility: The solubility of the new crystal form of besagliflozin in the examples or comparative examples was tested at room temperature. The test results are shown in Table 2.

[0065] (2) Stability: The new crystal form of besagliflozin in the examples or comparative examples was placed under high humidity conditions (constant temperature and humidity chamber, set temperature 25℃, relative humidity 75%), high temperature conditions (constant temperature drying chamber, set temperature 60℃, relative humidity of the drying environment ≤30%), and strong light conditions (strong light test chamber, illuminance set to 4500lx±500lx, temperature 25℃) for 10 days. Then, its appearance and purity were tested to evaluate its stability. Test results: as shown in Table 3.

[0066] Table 2. Solubility test results of the new crystal form of bexagliflozin in the examples or comparative examples.

[0067] As can be seen from the test results in Table 2 above, the new crystal form of besagliflozin prepared using the technical solution provided in this application has excellent solubility, which is beneficial to the dissolution and absorption of the drug in vivo.

[0068] Table 3. Stability test results of the new crystal form of bexagliflozin in the examples or comparative examples.

[0069] As can be seen from the test results in Table 3 above, the new crystal form of besagliflozin prepared using the technical solution provided in this application has good stability and can remain stable under high humidity, strong light and high temperature.

[0070] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A new crystalline form of Besagliflozin characterized in that, The X-ray powder diffraction pattern of the new crystal form of the besagliflozin comprises characteristic diffraction peaks at diffraction angle 2θ angle of 3.97±0.2, 8.00±0.2, 12.84±0.2, 15.94±0.2, 17.80±0.2, 18.40±0.2, 18.64±0.2, 19.77±0.2, 19.99±0.2, 22.56±0.2, 24.60±0.2, 25.32±0.2; wherein the X-ray powder diffraction is generated by CuKα1 ray.

2. The new crystalline form of claim 1, characterized in that, The X-ray powder diffraction pattern of the new crystal form of the besagliflozin comprises characteristic diffraction peaks at diffraction angle 2θ angle of 3.97±0.2, 8.00±0.2, 12.84±0.2, 14.57±0.2, 15.94±0.2, 16.33±0.2, 17.80±0.2, 18.40±0.2, 18.64±0.2, 19.01±0.2, 19.44±0.2, 19.77±0.2, 19.99±0.2, 21.33±0.2, 21.60±0.2, 22.56±0.2, 23.23±0.2, 23.62±0.2, 24.60±0.2, 25.32±0.2, 25.84±0.2, 26.41±0.

2.

3. The new crystalline form of claim 1, characterized in that, The melting point of the new crystal form of the besagliflozin is 50-70℃.

4. The new crystalline form of claim 1, characterized in that, The new crystal form of the besagliflozin loses 2.0-2.5% weight at 100-105℃.

5. Besagliflozin having a new crystalline form, characterized by, The besagliflozin has the new crystal form as claimed in any one of claims 1-4.

6. A process for the preparation of a new crystalline form of Besagliflozin as claimed in any one of claims 1 to 4, characterized in that, Specifically comprising the following steps in sequence: (1) dissolving the besagliflozin in an organic solvent according to solid-liquid ratio of 1g:2-10mL, cooling to -20-10℃ to obtain a mixed solution; the organic solvent is composed of one or both of methanol and ethanol; (2) adding water dropwise to the mixed solution to precipitate white solids; the volume ratio of water to organic solvent is 1:1.2-2.5; (3) collecting the white solids, washing with water, and vacuum drying at 30-50℃ to obtain the product.

7. A process for the preparation of the new crystalline form of Besagliflozin according to claim 6, characterized in that, In the step (1), the solid-liquid ratio is 1g:3-8mL; the cooling temperature is -10-0℃; the organic solvent is composed of methanol and n-heptane mixed according to volume ratio of 10:0.5-1.

5.

8. A process for the preparation of the new crystalline form of Besagliflozin according to claim 6, characterized in that, In the step (2), the volume ratio of water to organic solvent is 1:1.5-2.0; the water is added dropwise within 10-30min; in the step (3), the temperature for vacuum drying is 35-45℃, and the time is 3-12h.

9. A pharmaceutical composition, characterized by, The besagliflozin having the new crystal form as claimed in any one of claims 1-4 or claim 5.

10. Use of the new crystal form as claimed in any one of claims 1-4 or the besagliflozin having the new crystal form as claimed in claim 5 or the pharmaceutical composition as claimed in claim 9 in the preparation of a medicament for treating or preventing diabetes.

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