CN111559997A - Novel dapagliflozin crystal form and preparation method thereof - Google Patents
Novel dapagliflozin crystal form and preparation method thereof Download PDFInfo
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- CN111559997A CN111559997A CN201910112032.3A CN201910112032A CN111559997A CN 111559997 A CN111559997 A CN 111559997A CN 201910112032 A CN201910112032 A CN 201910112032A CN 111559997 A CN111559997 A CN 111559997A
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- C—CHEMISTRY; METALLURGY
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- 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
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- 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
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention relates to a novel dapagliflozin crystal form and a preparation method thereof. Specifically, the X-ray powder diffraction pattern of the novel crystalline form of dapagliflozin of the present invention measured using Cu-K α has characteristic diffraction peaks at the following 2 θ angles: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg.. The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel dapagliflozin crystal form and a preparation method thereof.
Background
Dapagliflozin is a commonly used medicament for treating diabetes clinically. The mechanism of action is to inhibit the sodium-glucose co-transporter 2(SGLT2) which reabsorbs glucose from the urine, thereby increasing urinary glucose excretion. On the basis of diet and exercise, dapagliflozin can be used as a monotherapy for type 2 diabetes patients to improve glycemic control.
The original research crystal form patent (CN20078024135.X) reports 10 co-crystals including (S) propylene glycol monohydrate, (R) propylene glycol monohydrate, ethanolate, ethanol dihydrate, ethylene glycol dihydrate (A), ethylene glycol dihydrate (B), L-proline (1:2) compound, L-proline (1:1) hemihydrate, and L-phenylalanine (1:1) compound. The original research does not obtain a non-aqueous crystal form of dapagliflozin, but adopts propylene glycol monohydrate eutectic, which indicates that the difficulty in developing the non-aqueous dapagliflozin crystal form is higher, and simultaneously the use of propylene glycol needs to be overcome, and a new dapagliflozin crystal form needs to be developed.
Various crystalline forms of dapagliflozin are disclosed in the prior art. For example, chinese patent CN106170482B discloses a crystalline form of dapagliflozin having a characteristic absorption peak at about 4.318(20.45) in an X-ray powder diffraction pattern expressed in terms of 2 θ angle and interplanar spacing (d value). Chinese patent CN104829573B discloses a dapagliflozin crystal form and discloses a spectrum obtained by performing X-ray powder diffraction measurement on Cu-K alpha rays.
However, the existing crystal forms have the problems of high water content, low purity, poor product stability and the like, and the preparation process has the problems of complex operation, high cost, low yield, great pollution and the like. Therefore, there is a need for a new crystalline form of dapagliflozin that overcomes the above-mentioned disadvantages of the prior art.
Disclosure of Invention
The invention provides a dapagliflozin crystal form which has characteristic diffraction peaks at the following 2theta angles by using an X-ray powder diffraction pattern measured by Cu-Ka: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg..
In one embodiment, the crystalline form has an X-ray powder diffraction pattern measured using Cu-ka having characteristic diffraction peaks at six or more, seven or more, eight or more, nine or more, ten or more, or eleven or more 2 Θ angles selected from the group consisting of: 5.347 +/-0.2 degrees, 7.623 +/-0.2 degrees, 8.143 +/-0.2 degrees, 9.446 +/-0.2 degrees, 10.484 +/-0.2 degrees, 15.308 +/-0.2 degrees, 15.850 +/-0.2 degrees, 17.416 +/-0.2 degrees, 20.122 +/-0.2 degrees, 24.601 +/-0.2 degrees, 29.612 +/-0.2 degrees and 30.398 +/-0.2 degrees.
In another embodiment, the crystalline form has an X-ray powder diffraction pattern, as measured using Cu-ka, as shown in figure 1.
In another embodiment, the crystalline form has X-ray powder diffraction pattern analysis data measured using Cu-ka as shown in table 1.
TABLE 1X-ray powder diffraction Pattern analysis data for dapagliflozin crystalline forms of the invention measured using Cu-Ka
In another embodiment, the crystalline form has a differential scanning calorimetry curve with an endothermic peak at 53.89 ± 3 ℃.
In another embodiment, the crystalline form has a differential scanning calorimetry curve as shown in figure 2.
In another embodiment, the crystalline form has a thermogravimetric analysis curve with a weight loss of about 0.943% at 150 ± 3 ℃.
In another embodiment, the thermogravimetric analysis curve of the crystalline form is shown in figure 3.
In another embodiment, the present invention also discloses a method of preparing a crystalline form of dapagliflozin, the method comprising: 1) dissolving amorphous dapagliflozin in water; 2) filtering with a filter membrane, standing the filtrate at low temperature for crystallization; and 3) carrying out suction filtration and reduced pressure drying.
The invention also provides application of the dapagliflozin crystal form in preparation of medicines for treating type 2 diabetes.
Drawings
Figure 1 shows an X-ray powder diffraction pattern of a crystalline form of dapagliflozin of the present invention.
Fig. 2 shows a differential scanning calorimetry curve for the dapagliflozin crystalline form of the invention.
Fig. 3 shows a thermogravimetric analysis curve of the crystalline form of dapagliflozin of the present invention.
Fig. 4 shows the crystal habit of the dapagliflozin crystalline form of the invention.
Detailed Description
The invention is further described below with reference to the figures and examples. It should be understood, however, that these examples are for the purpose of illustrating the invention in more detail, and are not to be construed as limiting the invention in any way.
The reagents and methods employed in the examples of the invention are conventional in the art. It will be clear to those skilled in the art that, unless otherwise specified, temperatures are expressed in degrees Celsius (C.) and operating temperatures are carried out at ambient temperature, which is 10 deg.C to 30 deg.C, preferably 20 deg.C to 25 deg.C; the allowable error of the melting point is +/-1%; the yield is mass percent.
Experimental methods
X-ray powder diffraction (XRPD)
XRPD data for the crystalline form was determined by brueck (d8advance) with the following diffraction parameters:
x-ray:
x-ray light pipe setting: 40kV and 25mA
Divergent slit: automatic
A monochromator: is free of
Scanning mode: continuous
Scan range (° 2 Theta): 4-40 degree
Scanning speed (sec/step): 0.5
2. Differential Scanning Calorimetry (DSC)
The DSC data of the crystalline form are determined by a differential scanning calorimeter of type TA (DSC 25) with the following thermal analysis parameters:
temperature range (. degree. C.): 30-300
Scanning rate (. degree. C./min): 10
Protective gas: nitrogen gas
3. Thermogravimetric analysis (TGA)
TGA data for the crystalline form was determined by a TA (TGA 550) instrument with the following thermal analysis parameters:
temperature range (. degree. C.): 30-350 deg.C
Scanning rate (. degree. C./min): 10
Protective gas: nitrogen gas
5. High Performance Liquid Chromatography (HPLC) detection
The conditions for HPLC detection were as follows:
technical effects
The crystal form of the invention has low water content, high purity, high product stability and good crystal habit.
Examples
The following examples are intended to illustrate specific embodiments of the present invention, but are not intended to limit the invention in any way.
Example 1 preparation of dapagliflozin crystalline form
Adding 0.2g of amorphous dapagliflozin (purchased from Shanghai Gao Lang chemical company, product number L01837-180301) into 30ml of purified water, stirring for 5min, filtering with a 0.45 micron filter membrane, transferring the filtrate into a beaker, sealing with the membrane, pricking pores, and slowly volatilizing to dryness to obtain 0.15g of rod-shaped crystals, wherein the yield is 75% and the purity is 99.6%. The crystalline form was measured for its X-ray powder diffraction pattern, differential scanning calorimetry curve and thermogravimetric analysis curve by the methods described above.
Example 2 preparation of dapagliflozin crystalline form
Dissolving 0.5g of amorphous dapagliflozin (purchased from Shanghai Gao Lang chemical company, product number L01837-180301) in 300ml of purified water, filtering with a 0.45-micron filter membrane, standing the filtrate at 0-10 ℃ for 24-36 h to precipitate crystals, filtering, and drying under reduced pressure. 0.3g is obtained, the yield is 60 percent and the purity is 99.2 percent.
Example 3 preparation of crystalline forms of dapagliflozin
Adding 0.5g of amorphous dapagliflozin into a 25ml flask, dissolving in 2ml of methanol, slowly dropwise adding 12ml of purified water, adding 10mg of seed crystal (the seed crystal is prepared by the method in example 1), standing at 0-10 ℃ for 12h, performing suction filtration, and drying under reduced pressure at 20-30 ℃. 0.45g is obtained, the yield is 90 percent and the purity is 99.5 percent.
Example 4 craving
Through microscope observation, the crystal nodule of the dapagliflozin crystal form prepared by the method in the embodiment 1 of the invention is rod-shaped (as shown in figure 4), has good fluidity, and is beneficial to a dry tabletting process of a preparation.
Example 5 stability test
An accelerated test (test conditions: temperature: 30 ℃ C., humidity: 65%) was conducted on the product in example 1, and the change in purity before and after acceleration was measured by HPLC. The results are shown in table 2 below, which shows that the purity of the crystal form is not obviously changed after 30 days of treatment, and the crystal form is stable.
TABLE 2 stability test results
| Purity of | Content of | |
| Day | ||
| 0 | 99.6％ | 0.2％ |
| 10 days | 99.4％ | 0.6％ |
| 15 days | 99.3％ | 0.7％ |
| 20 days | 99.2％ | 0.8％ |
| 30 days | 99.2％ | 0.8％ |
It should be understood that the above examples are for illustrative purposes only and are not intended to limit the scope of the present invention, and that various insubstantial modifications and adaptations of the invention may be made by those skilled in the art in light of the above teachings.
Claims (9)
1. A crystalline form of dapagliflozin having characteristic diffraction peaks at the following 2 Θ angles using an X-ray powder diffraction pattern measured at Cu-ka: 5.347 + -0.2 deg., 7.623 + -0.2 deg., 10.484 + -0.2 deg., 15.308 + -0.2 deg., 15.850 + -0.2 deg..
2. The crystalline form of dapagliflozin of claim 1, having an X-ray powder diffraction pattern measured using Cu-ka with characteristic diffraction peaks at six or more, seven or more, eight or more, nine or more, ten or more, or eleven or more 2 Θ angles selected from the group of: 5.347 +/-0.2 degrees, 7.623 +/-0.2 degrees, 8.143 +/-0.2 degrees, 9.446 +/-0.2 degrees, 10.484 +/-0.2 degrees, 15.308 +/-0.2 degrees, 15.850 +/-0.2 degrees, 17.416 +/-0.2 degrees, 20.122 +/-0.2 degrees, 24.601 +/-0.2 degrees, 29.612 +/-0.2 degrees and 30.398 +/-0.2 degrees.
3. The crystalline form of dapagliflozin of claim 2, having an X-ray powder diffraction pattern as shown in figure 1 of the accompanying drawings measured using Cu-ka.
4. The crystalline form of dapagliflozin of claim 1, having an endothermic peak at 53.89 ± 3 ℃ in a differential scanning calorimetry curve.
5. The crystalline form of dapagliflozin of claim 4, having a differential scanning calorimetry curve as shown in figure 2 of the accompanying drawings.
6. The crystalline dapagliflozin form of claim 1, having a thermogravimetric analysis curve with a weight loss of about 0.943% at 150 ± 3 ℃.
7. The crystalline form of dapagliflozin of claim 6, having the thermogravimetric analysis curve shown in figure 3 of the accompanying drawings.
8. A method of preparing a crystalline form of dapagliflozin, the method comprising: 1) dissolving amorphous dapagliflozin in water; 2) filtering with a filter membrane, standing the filtrate at low temperature for crystallization; and 3) carrying out suction filtration and reduced pressure drying.
9. Use of the crystalline form of dapagliflozin of any one of claims 1-7 or prepared by the method of claim 8 in the preparation of a medicament for the treatment of type 2 diabetes.
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| CN101479287A (en) * | 2006-06-28 | 2009-07-08 | 布里斯托尔-迈尔斯斯奎布公司 | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
| WO2014139447A1 (en) * | 2013-03-15 | 2014-09-18 | 天津药物研究院 | Crystal form a of (1s)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-d-glucose and preparation method and use thereof |
| CN104829572A (en) * | 2014-02-10 | 2015-08-12 | 江苏豪森药业股份有限公司 | Novel crystal form of dapagliflozin and preparation method thereof |
| CN104829573A (en) * | 2014-02-11 | 2015-08-12 | 江苏豪森药业股份有限公司 | Dapagliflozin new crystal form and preparation method thereof |
| WO2016155578A1 (en) * | 2015-03-27 | 2016-10-06 | 苏州晶云药物科技有限公司 | New crystal form of dapagliflozin and preparation method therefor |
| CN106146446A (en) * | 2015-04-17 | 2016-11-23 | 杭州领业医药科技有限公司 | The clean semihydrate of Da Gelie and crystal formation, its preparation method and pharmaceutical composition |
| CN106543124A (en) * | 2015-09-18 | 2017-03-29 | 天津市汉康医药生物技术有限公司 | dapagliflozin compound |
| WO2017202264A1 (en) * | 2016-05-24 | 2017-11-30 | 江苏豪森药业集团有限公司 | New dapagliflozin crystal form and preparation method and use thereof |
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2019
- 2019-02-13 CN CN201910112032.3A patent/CN111559997A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101479287A (en) * | 2006-06-28 | 2009-07-08 | 布里斯托尔-迈尔斯斯奎布公司 | Crystalline solvates and complexes of (is) -1, 5-anhydro-l-c- (3- ( (phenyl) methyl) phenyl) -d-glucitol derivatives with amino acids as sglt2 inhibitors for the treatment of diabetes |
| WO2014139447A1 (en) * | 2013-03-15 | 2014-09-18 | 天津药物研究院 | Crystal form a of (1s)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-dideoxy-d-glucose and preparation method and use thereof |
| CN104829572A (en) * | 2014-02-10 | 2015-08-12 | 江苏豪森药业股份有限公司 | Novel crystal form of dapagliflozin and preparation method thereof |
| CN104829573A (en) * | 2014-02-11 | 2015-08-12 | 江苏豪森药业股份有限公司 | Dapagliflozin new crystal form and preparation method thereof |
| WO2016155578A1 (en) * | 2015-03-27 | 2016-10-06 | 苏州晶云药物科技有限公司 | New crystal form of dapagliflozin and preparation method therefor |
| CN106146446A (en) * | 2015-04-17 | 2016-11-23 | 杭州领业医药科技有限公司 | The clean semihydrate of Da Gelie and crystal formation, its preparation method and pharmaceutical composition |
| CN106543124A (en) * | 2015-09-18 | 2017-03-29 | 天津市汉康医药生物技术有限公司 | dapagliflozin compound |
| WO2017202264A1 (en) * | 2016-05-24 | 2017-11-30 | 江苏豪森药业集团有限公司 | New dapagliflozin crystal form and preparation method and use thereof |
| CN108699020A (en) * | 2016-05-24 | 2018-10-23 | 江苏豪森药业集团有限公司 | Dapagliflozin novel crystal forms and its preparation method and application |
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