WO2020187150A1 - New crystal forms of dapagliflozin and preparation method thereof - Google Patents

New crystal forms of dapagliflozin and preparation method thereof Download PDF

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WO2020187150A1
WO2020187150A1 PCT/CN2020/079204 CN2020079204W WO2020187150A1 WO 2020187150 A1 WO2020187150 A1 WO 2020187150A1 CN 2020079204 W CN2020079204 W CN 2020079204W WO 2020187150 A1 WO2020187150 A1 WO 2020187150A1
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crystal form
dapagliflozin
ray powder
ethanol
organic solvent
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PCT/CN2020/079204
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French (fr)
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Shuwang GE
Jiting HUANG
Wei Tang
Wenqian Yang
Tie-Lin Wang
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Luoxin Pharmaceutical (Shanghai) Co., Ltd.
Shandong Luoxin Pharmaceutical Group Stock Co., Ltd.
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Publication of WO2020187150A1 publication Critical patent/WO2020187150A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention belongs to the pharmaceutical technical field, and particularly relates to new crystal forms of dapagliflozin and a preparation method thereof.
  • Dapagliflozin (with a formula shown below) is a diabetes medicament commonly used in clinical practice. Its action mechanism is to inhibit sodium-glucose cotransporter 2 (SGLT2) , which reabsorbs glucose from urine, thereby increasing urinary glucose excretion. Based on diet and exercise, dapagliflozin can be used as a single medicament for treating patients with type 2 diabetes to improve blood sugar control.
  • SGLT2 sodium-glucose cotransporter 2
  • the polymorphs patent by originator company (CN20078024135.
  • X) reports 10 kinds of cocrystals or solvates, including (S) -propylene glycol monohydrate, (R) -propylene glycol monohydrate, dimethanol solvate, mono-ethanol dihydrate, ethylene glycol dihydrate (A) , ethylene glycol dihydrate (B) , L-proline (1: 2) cocrystal, L-proline (1: 1) cocrystal, L-proline (1: 1) hemihydrate, and L-phenylalanine (1: 1) cocrystal.
  • the originator company fails to obtain an anhydrous crystal form of dapagliflozin, so propylene glycol monohydrate is employed.
  • X is especially a mono-ethanol dihydrate with a melting point of 40-41°C, which will melt during the preparation of the non-solvate crystal form by the vacuum drying method due to the low melting point, therefore, no anhydrous crystal form can be obtained.
  • the ethylene glycol dihydrate solvate was described in the description of CN20078024135. X.
  • the boiling point of ethylene glycol is 197°C, making the ethylene glycol dihydrate solvate difficult to remove the solvent by conventional drying method to obtain an anhydrous crystal form.
  • CN106543124 discloses a crystal form of dapagliflozin, which uses aqueous acetone (with a water content of 40%) , and has a difficulty in removing the free water by drying. Since the crystal form with a high content of free water will melt when the temperature is raised to 30°C, the water cannot be removed by drying at elevated temperature.
  • the four hydrate crystal forms are the hydrate crystal form disclosed in patent WO2016155578, the hydrate crystal form disclosed in patent CN201510182423.4, and the two hydrate crystal forms disclosed in patent CN201280058370. X, respectively.
  • the preparation methods of these four hydrate crystal forms are based on a single aqueous system, wherein the free water is difficult to be removed by drying and the material will melt by drying at elevated temperature, which are not suitable for large scale production.
  • the present invention provides a crystal form A of dapagliflozin, which is a hemi-ethanol solvate (with a formula shown below) , and characterized by X-ray powder diffraction pattern measured by Cu-K ⁇ having characteristic diffraction peaks at the following 2 ⁇ angles: 6.4 ⁇ 0.2°, 12.7 ⁇ 0.2°, 18.9 ⁇ 0.2°, 26.6 ⁇ 0.2°, and 27.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A measured by Cu-K ⁇ has 6 or more, 7 or more, 8 or more, or 9 or more of characteristic diffraction peaks at the 2 ⁇ angles selected from the group consisting of: 6.4 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.7 ⁇ 0.2°, 15.6 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 26.6 ⁇ 0.2°, and 27.2 ⁇ 0.2°.
  • Table 1 The analytical data of X-ray powder diffraction pattern of the crystal form A of dapagliflozin of the present invention measured by Cu-K ⁇
  • the crystal form A has an X-ray powder diffraction pattern measured by Cu-K ⁇ as shown in Figure 1.
  • the differential scanning calorimetric curve of the crystal form A has an endothermic peak at 62.93 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form A has a weight loss of about 5.82%up to 100 ⁇ 3°C.
  • the ethanol content detected by gas chromatography is 5.15%, indicating that the residual solvent is ethanol.
  • the water content detected by Karl Fischer titrators is 0.65%, and the remaining weight loss is consistent with the ethanol theoretical value of 5.1%in theoretical hemi-ethanol solvate.
  • the present invention also provides a method for preparing the crystal form A of dapagliflozin which comprises: 1) dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; and 3) filtering and drying.
  • the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols.
  • the second organic solvent is isooctane, n-heptane or n-hexane.
  • the first organic solvent is ethanol.
  • the second organic solvent is isooctane.
  • the low temperature is 0-10°C.
  • step 3 the drying is carried out under vacuum at 10-30°C.
  • the present invention also provides a crystal form B of dapagliflozin, which is an anhydrous crystal form and characterized by X-ray powder diffraction pattern measured by Cu-K ⁇ having characteristic diffraction peaks at the following 2 ⁇ angles: 6.3 ⁇ 0.2°, 7.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.3 ⁇ 0.2°, and 23.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B measured by Cu-K ⁇ has 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, or 14 or more of characteristic diffraction peaks at the 2 ⁇ angles selected from the group consisting of: 6.3 ⁇ 0.2°, 7.2 ⁇ 0.2°, 14.5 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.5 ⁇ 0.2°, 18.7 ⁇ 0.2°, 19.6 ⁇ 0.2°, 21.3 ⁇ 0.2°, 22.3 ⁇ 0.2°, 22.4 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.8 ⁇ 0.2°, 26.8 ⁇ 0.2°, 28.8 ⁇ 0.2°, and 31.0 ⁇ 0.2°.
  • the crystal form B has an X-ray powder diffraction pattern measured by Cu-K ⁇ as shown in Figure 5.
  • the differential scanning calorimetric curve of the crystal form B has an endothermic peak at 85.06 ⁇ 3°C.
  • thermogravimetric analysis curve of the crystal form B has a weight loss of about 0.27%up to 150 ⁇ 3°C.
  • the water content detected by Karl Fischer titrators is 0.18%, which is consistent with the TG weight loss data.
  • the present invention also provides a method for preparing the crystal form B of dapagliflozin which comprises: 1) dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; and 3) filtering and drying.
  • the method further comprises: 4) drying under vacuum at 45-60°C.
  • the method further comprises: 4) vacuum drying at 45-55°C.
  • the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols.
  • the second organic solvent is isooctane, n-heptane or n-hexane.
  • the first organic solvent is ethanol.
  • the second organic solvent is isooctane.
  • the low temperature is 0-10°C.
  • step 3 the drying is carried out under vacuum at 10-30°C.
  • the present invention also provides a use of the crystal forms of dapagliflozin as mentioned above in manufacturing a medicament for treating type 2 diabetes.
  • Fig. 1 shows the X-ray powder diffraction pattern of the crystal form A of dapagliflozin of the present invention.
  • Fig. 2 shows the X-ray powder diffraction pattern (partial enlarged view) of the crystal form A of dapagliflozin of the present invention.
  • Fig. 3 shows the differential scanning calorimetric curve of the crystal form A of dapagliflozin of the present invention.
  • Fig. 4 shows the thermogravimetric analysis curve of the crystal form A of dapagliflozin of the present invention.
  • Fig. 5 shows the X-ray powder diffraction pattern of the crystal form B of dapagliflozin of the present invention.
  • Fig. 6 shows the differential scanning calorimetric curve of the crystal form B of dapagliflozin of the present invention.
  • Fig. 7 shows the thermogravimetric analysis curve of the crystal form B of dapagliflozin of the present invention.
  • the reagents and methods used in the embodiments of the present disclosure are conventional reagents and methods in the art. Those skilled in the art should know that unless otherwise indicated hereinafter, the temperature is expressed in degree Celsius (°C) , the operating temperature is room temperature, and the room temperature refers to 10°C-30°C; the yield is expressed in mass percentage.
  • the XRPD data of the crystal forms are detected by Bruker Corporation (D8 advance) , and the diffraction parameters are as follows:
  • Step length (°) 0.05
  • DSC Differential scanning calorimeter
  • the DSC data of the crystal forms are detected by TA (DSC 25) type differential scanning calorimeter, and the thermal analysis parameters are as follows:
  • TGA data of the crystal forms are detected by TA (TGA 550) instrument, and the thermal analysis parameters are as follows:
  • HPLC detection The conditions of HPLC detection are as follows:
  • the crystal form A of the present invention contains a hemi-ethanol solvate, which stays stable during drying at 10-30°C.
  • the ethanol solvent can be easily removed by drying at 45-55°Cto obtain the anhydrous crystal form B.
  • the crystal form A is an intermediate state crystal form of the anhydrous crystal form B.
  • the crystal form A of the hemi-ethanol solvate can be directly used in forumulation preparation by performing wet granulation and removing the solvent by drying, and can meet the quality requirements of the formulation preparation.
  • the crystal form B of the present invention has a low water content, a high purity, a good product stability at high temperature of 60°C, a simple preparation process with mild operating conditions, and is suitable for large-scale industrial production.
  • Embodiment 1 preparation of the crystal form A of dapagliflozin
  • Embodiment 2 preparation of the crystal form A of dapagliflozin
  • Embodiment 3 preparation of the crystal form A of dapagliflozin
  • Embodiment 4 preparation of the crystal form B of dapagliflozin
  • Embodiment 5 confirmation of the solvate
  • Embodiment 6 stability test
  • Embodiments 1 and 4 i.e. the crystal form A and B of dapagliflozin
  • the results are shown in table 3 and table 4, which indicate that both crystal forms are stable.
  • Embodiment 7 comparison of the crystal form B and the propylene glycol solvate developed by originator company
  • the propylene glycol solvate described in the polymorphs patent by originator company was prepared thereof (CN20078024135. X) . After being placed along with the crystal form B at 60°Cfor 12 hours, the propylene glycol solvate started to melt, and its physical properties changed, while the crystal form B solid powder did not change, which was stable and achieved an unexpected effect.
  • the crystal form B has superior stability compared with the propylene glycol solvate adopted by originator company, and avoids the use of propylene glycol in the propylene glycol solvate, which reduces production cost and improves overall production efficiency.

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Abstract

Disclosed are new crystal forms of dapagliflozin and a preparation method thereof. Particularly, the X-ray powder diffraction pattern of the crystal form A of dapagliflozin has characteristic diffraction peaks at the following 2θ angles: 6.3±0.2°, 12.5±0.2°, 16.0±0.2°, 18.8±0.2°, 26.4±0.2°, and 27.1±0.2°. The X-ray powder diffraction pattern of the crystal form B of dapagliflozin has characteristic diffraction peaks at the following 2θ angles: 6.3±0.2°, 7.2±0.2°, 14.5±0.2°, 19.6±0.2°, 21.3±0.2°, and 23.6±0.2°. The crystal form A is hemi-ethanol solvate, which is stable when it is baked at 10-30℃. The ethanol solvent can be easily removed by baking at 45-55℃ to obtain the anhydrous crystal form B. The crystal form A is an intermediate state crystal form of the anhydrous crystal form B. At the same time, the crystal form A of hemi-ethanol solvate can be directly used in preparation by performing wet granulation and removing the solvent by baking, and can meet the quality requirements of the preparation. The crystal form B has a low water content, a high purity, a good product stability at 60℃ high temperature, a simple preparation process with mild operation conditions, and is suitable for large scale industrial production.

Description

New Crystal Forms of Dapagliflozin and Preparation Method thereof
This application claims the priority of Chinese Patent Application No. 201910196479.3 filed on March 15, 2019, the contents of which are incorporated herein by reference in their entirety.
Field of invention
The present invention belongs to the pharmaceutical technical field, and particularly relates to new crystal forms of dapagliflozin and a preparation method thereof.
Prior arts
Dapagliflozin (with a formula shown below) is a diabetes medicament commonly used in clinical practice. Its action mechanism is to inhibit sodium-glucose cotransporter 2 (SGLT2) , which reabsorbs glucose from urine, thereby increasing urinary glucose excretion. Based on diet and exercise, dapagliflozin can be used as a single medicament for treating patients with type 2 diabetes to improve blood sugar control.
Figure PCTCN2020079204-appb-000001
The polymorphs patent by originator company (CN20078024135. X) reports 10 kinds of cocrystals or solvates, including (S) -propylene glycol monohydrate, (R) -propylene glycol monohydrate, dimethanol solvate, mono-ethanol dihydrate, ethylene glycol dihydrate (A) , ethylene glycol dihydrate (B) , L-proline (1: 2) cocrystal, L-proline (1: 1) cocrystal, L-proline (1: 1) hemihydrate, and L-phenylalanine (1: 1) cocrystal. The originator company fails to obtain an anhydrous crystal form of dapagliflozin, so propylene glycol monohydrate is employed.
It is described in the description of CN20078024135. X that after the dimethanol solvate was dried under vacuum at 30℃, the obtained powder lost crystallinity.
The ethanol solvate described in the description of CN20078024135. X is especially a mono-ethanol dihydrate with a melting point of 40-41℃, which will melt during the  preparation of the non-solvate crystal form by the vacuum drying method due to the low melting point, therefore, no anhydrous crystal form can be obtained.
The ethylene glycol dihydrate solvate was described in the description of CN20078024135. X. The boiling point of ethylene glycol is 197℃, making the ethylene glycol dihydrate solvate difficult to remove the solvent by conventional drying method to obtain an anhydrous crystal form.
In the prior art, three anhydrous crystal forms of dapagliflozin and four hydrate crystal forms of dapagliflozin are disclosed. Chinese patent CN106170482B discloses a crystal form of dapagliflozin, the XRD of which shows only one characteristic diffraction peak, indicating the presence of the amorphous form in the crystal form, therefore, the crystal form is not granted. Chinese patent CN104829573B discloses a crystal form of dapagliflozin, the preparation method of which is based on an aqueous system and conversion at low temperature. The preparation method takes a long time and is not suitable for industrial production. CN106543124 discloses a crystal form of dapagliflozin, which uses aqueous acetone (with a water content of 40%) , and has a difficulty in removing the free water by drying. Since the crystal form with a high content of free water will melt when the temperature is raised to 30℃, the water cannot be removed by drying at elevated temperature.
The four hydrate crystal forms are the hydrate crystal form disclosed in patent WO2016155578, the hydrate crystal form disclosed in patent CN201510182423.4, and the two hydrate crystal forms disclosed in patent CN201280058370. X, respectively. The preparation methods of these four hydrate crystal forms are based on a single aqueous system, wherein the free water is difficult to be removed by drying and the material will melt by drying at elevated temperature, which are not suitable for large scale production.
According to the prior art, it is difficult to obtain an anhydrous crystal form from a solvate by drying to remove solvent. It is also relatively difficult to obtain an anhydrous crystal form with good stability and suitable for industrial production. Therefore, the originator company choses the crystal form of the propylene glycol monohydrate rather than the anhydrous crystal form as the crystal form for developing the pharmaceutical preparation. However, the introduction of propylene glycol will increase the production cost and require the control of impurities related to propylene glycol. The experimental results show that the propylene glycol monohydrate developed by originator company will melt after 1 day under the condition of 60℃, indicated that it is unstable under such condition.
The above-mentioned shortcomings including high water content, unsuitability for drying under elevated temperature, unsuitability for large scale production, and instability under high  temperature, need to be resolved urgently. There is a need to develop a new anhydrous crystal form and its preparation method, which can overcome the shortcomings of the prior art.
Content of the present invention
The present invention provides a crystal form A of dapagliflozin, which is a hemi-ethanol solvate (with a formula shown below) , and characterized by X-ray powder diffraction pattern measured by Cu-Kα having characteristic diffraction peaks at the following 2θ angles: 6.4±0.2°, 12.7±0.2°, 18.9±0.2°, 26.6±0.2°, and 27.2±0.2°.
Figure PCTCN2020079204-appb-000002
In an embodiment, the X-ray powder diffraction pattern of the crystal form A measured by Cu-Kα has 6 or more, 7 or more, 8 or more, or 9 or more of characteristic diffraction peaks at the 2θ angles selected from the group consisting of: 6.4±0.2°, 11.5±0.2°, 12.7±0.2°, 15.6±0.2°, 16.1±0.2°, 17.5±0.2°, 18.9±0.2°, 21.8±0.2°, 26.6±0.2°, and 27.2±0.2°.
In another embodiment, the analytical data of X-ray powder diffraction pattern of the crystal form A measured by Cu-Kα are shown in Table 1.
Table 1. The analytical data of X-ray powder diffraction pattern of the crystal form A of dapagliflozin of the present invention measured by Cu-Kα
No. 2θ angle (°) d (A) Relative intensity
1 5.7 15.41084 1.0%
2 6.4 13.71429 100.0%
3 7.0 12.65150 3.3%
4 10.0 8.87383 2.1%
5 11.0 8.02642 1.1%
6 11.5 7.69556 5.1%
7 12.7 6.98767 10.7%
8 13.8 6.43375 0.3%
9 14.9 5.94911 2.3%
10 15.6 5.68336 4.2%
11 16.1 5.51042 4.5%
12 17.4 5.07805 2.4%
13 18.3 4.83250 1.4%
14 18.9 4.68980 17.2%
15 19.7 4.49597 1.4%
16 20.6 4.31202 1.2%
17 21.8 4.06615 7.7%
18 23.1 3.84114 1.5%
19 23.8 3.73419 3.5%
20 25.0 3.55430 1.5%
21 26.6 3.35338 5.4%
22 27.2 3.27926 4.5%
23 27.8 3.21145 1.1%
24 28.6 3.12355 1.0%
25 29.6 3.01981 1.2%
26 30.3 2.95208 2.4%
27 30.9 2.89076 1.2%
28 31.4 2.84520 0.8%
29 32.2 2.77745 1.1%
30 33.3 2.68828 0.3%
31 33.3 2.68485 0.3%
32 34.5 2.59710 1.1%
33 35.2 2.54814 1.8%
34 36.4 2.46445 2.7%
35 38.1 2.36263 0.4%
36 39.2 2.29821 0.2%
37 39.3 2.29091 0.2%
In an embodiment, the crystal form A has an X-ray powder diffraction pattern measured by Cu-Kα as shown in Figure 1.
In an embodiment, the differential scanning calorimetric curve of the crystal form A has an endothermic peak at 62.93±3℃.
In an embodiment, the thermogravimetric analysis curve of the crystal form A has a weight loss of about 5.82%up to 100±3℃. The ethanol content detected by gas chromatography is 5.15%, indicating that the residual solvent is ethanol. The water content detected by Karl Fischer titrators is 0.65%, and the remaining weight loss is consistent with the ethanol theoretical value of 5.1%in theoretical hemi-ethanol solvate.
The present invention also provides a method for preparing the crystal form A of dapagliflozin which comprises: 1) dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; and 3) filtering and drying.
In an embodiment, the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols.
In an embodiment, the second organic solvent is isooctane, n-heptane or n-hexane.
In an embodiment, the first organic solvent is ethanol.
In an embodiment, the second organic solvent is isooctane.
In an embodiment, the low temperature is 0-10℃.
In an embodiment, in step 3) , the drying is carried out under vacuum at 10-30℃.
The present invention also provides a crystal form B of dapagliflozin, which is an anhydrous crystal form and characterized by X-ray powder diffraction pattern measured by Cu-Kα having characteristic diffraction peaks at the following 2θ angles: 6.3±0.2°, 7.2±0.2°, 14.5±0.2°, 19.6±0.2°, 21.3±0.2°, and 23.6±0.2°.
In an embodiment, the X-ray powder diffraction pattern of the crystal form B measured by Cu-Kα has 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, or 14 or more of characteristic diffraction peaks at the 2θ angles selected from the group consisting of: 6.3±0.2°, 7.2±0.2°, 14.5±0.2°, 16.3±0.2°, 17.5±0.2°, 18.7±0.2°, 19.6±0.2°, 21.3±0.2°, 22.3±0.2°, 22.4±0.2°, 23.6±0.2°, 24.8±0.2°, 26.8±0.2°, 28.8±0.2°, and 31.0±0.2°.
In another embodiment, the analytical data of X-ray powder diffraction pattern of the crystal form B measured by Cu-Kα are shown in Table 2.
Table 2. The analytical data of X-ray powder diffraction pattern of the crystal form B of dapagliflozin of the present invention measured by Cu-Kα
No. 2θ angle (°) d (A) Relative intensity
1 6.3 14.05400 100.0%
2 7.2 12.19723 55.1%
3 12.4 7.14046 3.4%
4 13.0 6.78522 4.6%
5 14.5 6.08592 34.4%
6 16.3 5.42375 43.5%
7 17.5 5.05458 12.1%
8 18.7 4.74225 16.9%
9 19.6 4.53092 44.3%
10 21.3 4.16370 31.1%
11 22.3 3.97557 32.4%
12 22.4 3.96783 30.3%
13 23.6 3.76540 27.8%
14 24.8 3.59351 13.7%
15 26.8 3.32590 21.6%
16 28.2 3.16239 2.7%
17 28.8 3.10197 9.8%
18 29.3 3.04083 1.4%
19 30.1 2.96386 2.6%
20 31.0 2.87913 9.7%
21 33.0 2.71350 4.1%
22 35.3 2.54136 1.9%
23 38.0 2.36405 3.4%
In an embodiment, the crystal form B has an X-ray powder diffraction pattern measured by Cu-Kα as shown in Figure 5.
In an embodiment, the differential scanning calorimetric curve of the crystal form B has an endothermic peak at 85.06±3℃.
In an embodiment, the thermogravimetric analysis curve of the crystal form B has a weight loss of about 0.27%up to 150±3℃. The water content detected by Karl Fischer titrators is 0.18%, which is consistent with the TG weight loss data.
The present invention also provides a method for preparing the crystal form B of dapagliflozin which comprises: 1) dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; and 3) filtering and drying.
In an embodiment, the method further comprises: 4) drying under vacuum at 45-60℃.
In a preferred embodiment, the method further comprises: 4) vacuum drying at 45-55℃.
In an embodiment, the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols.
In an embodiment, the second organic solvent is isooctane, n-heptane or n-hexane.
In an embodiment, the first organic solvent is ethanol.
In an embodiment, the second organic solvent is isooctane.
In an embodiment, the low temperature is 0-10℃.
In an embodiment, in step 3) , the drying is carried out under vacuum at 10-30℃.
The present invention also provides a use of the crystal forms of dapagliflozin as mentioned above in manufacturing a medicament for treating type 2 diabetes.
Brief description of the drawings
Fig. 1 shows the X-ray powder diffraction pattern of the crystal form A of dapagliflozin of the present invention.
Fig. 2 shows the X-ray powder diffraction pattern (partial enlarged view) of the crystal form A of dapagliflozin of the present invention.
Fig. 3 shows the differential scanning calorimetric curve of the crystal form A of dapagliflozin of the present invention.
Fig. 4 shows the thermogravimetric analysis curve of the crystal form A of dapagliflozin of the present invention.
Fig. 5 shows the X-ray powder diffraction pattern of the crystal form B of dapagliflozin of the present invention.
Fig. 6 shows the differential scanning calorimetric curve of the crystal form B of dapagliflozin of the present invention.
Fig. 7 shows the thermogravimetric analysis curve of the crystal form B of dapagliflozin of the present invention.
Detailed description of the preferred embodiment
The present invention is further described with reference to the figures and the embodiments. However, it should be understood that these embodiments are only used to describe the present invention in more detail and should not be used for restricting the present invention in any form.
The reagents and methods used in the embodiments of the present disclosure are conventional reagents and methods in the art. Those skilled in the art should know that unless otherwise indicated hereinafter, the temperature is expressed in degree Celsius (℃) , the operating temperature is room temperature, and the room temperature refers to 10℃-30℃; the yield is expressed in mass percentage.
Experimental methods
1. X-ray powder diffraction (XRPD)
The XRPD data of the crystal forms are detected by Bruker Corporation (D8 advance) , and the diffraction parameters are as follows:
X-ray: Cu, Kα, 
Figure PCTCN2020079204-appb-000003
X-ray Tube: 40 kV, 25 mA
Divergence slit: automatic
Monochromator: none
Scanning mode: continuous
Scanning range (°2Theta) : 4-40
Scanning speed (sec/step) : 0.5
Step length (°) : 0.05
2. Differential scanning calorimeter (DSC)
The DSC data of the crystal forms are detected by TA (DSC 25) type differential scanning calorimeter, and the thermal analysis parameters are as follows:
Temperature range (℃) : 30-350
Scanning speed (℃/min) : 10
Protective gas: nitrogen gas
3. Thermogravimetric analysis (TGA)
The TGA data of the crystal forms are detected by TA (TGA 550) instrument, and the thermal analysis parameters are as follows:
Temperature range (℃) : 30-350
Scanning speed (℃/min) : 10
Protective gas: nitrogen gas
4. High performance liquid chromatography (HPLC) detection
The conditions of HPLC detection are as follows:
Figure PCTCN2020079204-appb-000004
Figure PCTCN2020079204-appb-000005
5. Chromatography detection for analyzing ethanol content
Figure PCTCN2020079204-appb-000006
Technical effect
The crystal form A of the present invention contains a hemi-ethanol solvate, which stays stable during drying at 10-30℃. The ethanol solvent can be easily removed by drying at 45-55℃to obtain the anhydrous crystal form B. Thus, the crystal form A is an intermediate state crystal form of the anhydrous crystal form B. At the same time, the crystal form A of the hemi-ethanol solvate can be directly used in forumulation preparation by performing wet granulation and removing the solvent by drying, and can meet the quality requirements of the formulation preparation.
The crystal form B of the present invention has a low water content, a high purity, a good product stability at high temperature of 60℃, a simple preparation process with mild operating conditions, and is suitable for large-scale industrial production.
Embodiment
The following embodiments further illustrate the present invention, but the present invention is not limited thereto.
Embodiment 1: preparation of the crystal form A of dapagliflozin
5g of dapagliflozin (purchased from Anhui biopharmaceutical Co., Ltd., batch number: 20180902) was dissolved in 10mL of absolute ethanol, followed by filtration. 30mL of isooctane was added dropwise at the temperature controlled at 0-10℃, and a white solid was precipitated out. 30mL of isooctane was continuously added dropwise. The temperature was controlled at 0-10℃for 2-3 hours for the precipitation of crystal. After filtration, the white solid was dried under vacuum at 10-30℃ for 6 hours to obtain 4.6g of product with a yield of 92%, a purity of 99.82%, and a maximum single impurity of 0.05%.
Embodiment 2: preparation of the crystal form A of dapagliflozin
5g of dapagliflozin was dissolved in 10mL of absolute ethanol, followed by filtration. 12mL of isooctane was added dropwise at the temperature controlled at 0-10℃, followed by addition of 25mg of the seed crystal obtained in the Embodiment 1, and 48mL of isooctane was added dropwise continuously. The temperature was controlled at 0-10℃for 2-3 hours for the precipitation of crystal. After suction filtration, the white solid was dried under vacuum at 10-30℃ for 7 hours to obtain 4.5g of product with a yield of 90%, a purity of 99.85%, and a maximum single impurity of 0.07%.
Embodiment 3: preparation of the crystal form A of dapagliflozin
5g of dapagliflozin was dissolved in 10mL of absolute ethanol, followed by filtration. 30mL of n-heptane was added dropwise at the temperature controlled at 0-10℃, and a solid was precipitated out. 30mL of n-heptane was added dropwise continuously. The temperature was controlled at 0-10℃for 2-3 hours for the precipitation of crystal. After suction filtration, the white solid was dried under vacuum at 10-30℃ for 5 hours to obtain 4.4g of product with a yield of 88%, a purity of 99.80%, and a maximum single impurity of 0.06%.
Embodiment 4: preparation of the crystal form B of dapagliflozin
2 g of solid obtained in the Embodiment 1 was dried under vacuum at 45-55℃for 6-16 hours to obtain 1.9g of product with a yield of 95%, a purity of 99.83%, and a maximum single impurity of 0.06%.
Embodiment 5: confirmation of the solvate
Injection according to the gas chromatography method was performed with dimethyl sulfoxide as diluent. Chromatographic grade ethanol was prepared into 0.5mg/mL sample for injection. The crystal form A was prepared into 50mg/mL sample for injection. According to the calculation of peak area, the crystal form A contains 5.15%ethanol, which is consistent with the theoretical value of hemiethanolate (5.1%) .
Embodiment 6: stability test
The products obtained in the Embodiments 1 and 4 (i.e. the crystal form A and B of dapagliflozin) were respectively subjected to stability test, and the purity changes before and after acceleration condition were measured by HPLC. The results are shown in table 3 and table 4, which indicate that both crystal forms are stable.
Table 3. The results of the stability test of the crystal form A of dapagliflozin
Figure PCTCN2020079204-appb-000007
Table 4. The results of the stability test of the crystal form B of dapagliflozin
Figure PCTCN2020079204-appb-000008
Figure PCTCN2020079204-appb-000009
Embodiment 7: comparison of the crystal form B and the propylene glycol solvate developed by originator company
The propylene glycol solvate described in the polymorphs patent by originator company was prepared thereof (CN20078024135. X) . After being placed along with the crystal form B at 60℃for 12 hours, the propylene glycol solvate started to melt, and its physical properties changed, while the crystal form B solid powder did not change, which was stable and achieved an unexpected effect. The crystal form B has superior stability compared with the propylene glycol solvate adopted by originator company, and avoids the use of propylene glycol in the propylene glycol solvate, which reduces production cost and improves overall production efficiency.
It should be understood that the above embodiments are only used to further describe the present invention, but not to limit the protection scope thereof. Nonessential improvements and adjustments made by those skilled in the art based on the above content of the present invention belong to the protection scope of the present invention.

Claims (14)

  1. A crystal form A of dapagliflozin, wherein the X-ray powder diffraction pattern measured by Cu-Kα has characteristic diffraction peaks at the following 2θ angles: 6.4±0.2°, 12.7±0.2°, 18.9±0.2°, 26.6±0.2°, and 27.2±0.2°.
  2. The crystal form A of dapagliflozin as defined in claim 1, wherein the X-ray powder diffraction pattern measured by Cu-Kα has 6 or more, 7 or more, 8 or more, or 9 or more of characteristic diffraction peaks at the 2θ angles selected from the group consisting of 6.4±0.2°, 11.5±0.2°, 12.7±0.2°, 15.6±0.2°, 16.1±0.2°, 17.5±0.2°, 18.9±0.2°, 21.8±0.2°, 26.6±0.2°, and 27.2±0.2°.
  3. The crystal form A of dapagliflozin as defined in claim 2, wherein the X-ray powder diffraction pattern measured by Cu-Kα is as shown in Figure 1.
  4. The crystal form A of dapagliflozin as defined in claim 1, wherein the differential scanning calorimetric curve has an endothermic peak at 62.93±3℃.
  5. The crystal form A of dapagliflozin as defined in claim 1, wherein the thermogravimetric analysis curve has a weight loss of about 5.82%up to 100±3℃.
  6. A crystal form B of dapagliflozin, wherein the X-ray powder diffraction pattern measured by Cu-Kα has characteristic diffraction peaks at the following 2θ angles: 6.3±0.2°, 7.2±0.2°, 14.5±0.2°, 19.6±0.2°, 21.3±0.2°, and 23.6±0.2°.
  7. The crystal form B of dapagliflozin as defined in claim 6, wherein the X-ray powder diffraction pattern measured by Cu-Kα has 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, or 14 or more of characteristic diffraction peaks at the 2θ angles selected from the group consisting of 6.3±0.2°, 7.2±0.2°, 14.5±0.2°, 16.3±0.2°, 17.5±0.2°, 18.7±0.2°, 19.6±0.2°, 21.3±0.2°, 22.3±0.2°, 22.4±0.2°, 23.6±0.2°, 24.8±0.2°, 26.8±0.2°, 28.8±0.2°, and 31.0±0.2°.
  8. The crystal form B of dapagliflozin as defined in claim 7, wherein the X-ray powder diffraction pattern measured by Cu-Kα is as shown in Figure 5.
  9. The crystal form B of dapagliflozin as defined in claim 6, wherein the differential scanning calorimetric curve has an endothermic peak at 85.06±3℃.
  10. The crystal form B of dapagliflozin as defined in claim 6, wherein the thermogravimetric analysis curve has a weight loss of about 0.27%up to 150±3℃.
  11. A process for preparing the crystal form A of dapagliflozin, which comprises 1)  dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; and 3) filtering and drying.
  12. The process as defined in claim 11, wherein the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols, and/or the second organic solvent is isooctane, n-heptane or n-hexane.
  13. A process for preparing the crystal form B of dapagliflozin, which comprises 1) dissolving dapagliflozin in a first organic solvent; 2) adding a second organic solvent, allowing crystal to precipitate at low temperature; 3) filtering and drying; and 4) drying under vacuum at 45-60℃.
  14. The process as defined in claim 13, wherein the first organic solvent is ethanol or a mixed solvent of ethanol and other alcohols, and/or the second organic solvent is isooctane, n-heptane or n-hexane.
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WO2018029611A1 (en) * 2016-08-09 2018-02-15 Laurus Labs Limited Novel processes for preparation of dapagliflozin or its solvates or co-crystals thereof
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