CN103896930A - Method for preparing pharmaceutical crystal form of Canagliflozin hemihydrates - Google Patents
Method for preparing pharmaceutical crystal form of Canagliflozin hemihydrates Download PDFInfo
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention discloses a method for preparing a pharmaceutical crystal form of Canagliflozin hemihydrates. The method comprises the following steps: firstly, adding pharmaceutical raw materials of Canagliflozin into organic solvents, heating to be dissolved, then adding water and cooling to 30-40 DEG C; secondly, adding an organic solvent under stirring or adding crystal seeds after stirring for 30-60 minutes; thirdly, stirring at 10-30 DEG C for 4 to 10 hours, crystallizing, filtering, collecting the precipitated crystals, vacuum drying at 40-60 DEG C to obtain the crystal form of Canagliflozin which meets the requirements of medicinal preparation, and has the purity of 99.9%. According to the invention, the yield of the crystal form of Canagliflozin is greatly improved by strictly controlling the crystallization temperature, the crystallization time and amount of solvent in the process and the method disclosed by the invention has the characteristics of simple operation, low cost, high product purity and is suitable for the industrial production of Canagliflozin.
Description
Technical field
The present invention relates to technical field prepared by drug crystal forms, relate to particularly the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie.
Background technology
Ka Gelie is clean, English name Canagliflozin, and molecular formula is C
24h
25fO
5s, molecular weight is 444.52, structural formula is as follows:
Ka Gelie clean (canagliflozin) is the first SGLT2 inhibitor of FDA approval, is used for the treatment of the type ii diabetes of adult patients.SGLT glucose transporter, having two kinds of hypotypes is SGLT1 and SGLT2, is distributed in respectively mucous membrane of small intestine and uriniferous tubules, glucose transport can be entered to blood.Ka Gelie net energy suppresses SLCT2, glucose in uriniferous tubules can not heavily be absorbed smoothly enter blood and discharges with urine, thereby reduce blood sugar concentration.Because glucose enters urine through kidney, be attended by the side effects such as kidney function damage, symptomatic hypotension, fungi infestation.9 clinical trials that relate to 10285 patients have proved security and the validity of Invokana, both can alonely also can combine other hypoglycemic drugs.In the double blind controling test of 26 weeks by a definite date, 584 type ii diabetes patients are divided into three groups, be clean group of 100mg Ka Gelie, clean group of 300mg Ka Gelie and placebo, than placebo, 100mg Ka Gelie only organizes average amount and reduces HbA1c 0.91% outward, and 300mg Ka Gelie only organizes average amount and reduces HbA1c 1.16% outward.
Ka Gelie the accounts show a surplus of at anhydride and semihydrate, can determine that it is semihydrate according to listing preparation, and wherein semihydrate has amorphous and two kinds of forms of medicinal crystal-form.Publication number is WO2008069327A1, within open day, be that PCT Patent Application Publication, the publication number on June 12nd, 2008 is CN101573368A, within open day, is that the Chinese patent application document on November 04th, 2009 all discloses compound (I) semihydrate and specific crystal formation thereof, but do not relate to the preparation method of concrete crystal formation.
Summary of the invention
In view of this, the object of this invention is to provide that a kind of yield is high, purity is high, the preparation method of the clean semihydrate medicinal crystal-form of the simple Ka Gelie of method.
For realizing object of the present invention, adopt following scheme: the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie, comprises the steps:
Step 1, card taking lattice are listed as clean bulk drug, add organic solvent, and then heating for dissolving adds and is water-cooled to 30 ~ 40 ℃;
Step 3, under 10 ~ 30 ℃ of conditions of temperature, stirs 4 ~ 10 hours crystallizatioies, filters, and collects the crystallization of separating out, 40 ~ 60 ℃ of vacuum-dryings, the i.e. clean semihydrate medicinal crystal-form of get Ka Gelie.
In step 1, described organic solvent is selected from least one in ethyl acetate, acetone, methyl alcohol, ethanol and toluene.
In step 2, described organic solvent is selected from least one in ether, methyl tertiary butyl ether, sherwood oil, normal hexane and hexanaphthene.
The clean bulk drug of Ka Gelie described in step 1: organic solvent described in step 1: the ratio of the consumption of organic solvent described in step 2 is 1 weight part: (1 ~ 10) parts by volume: (1 ~ 10) parts by volume, preferably 1 weight part: (2 ~ 5) parts by volume: (2 ~ 5) parts by volume.
In step 1, ratio 1:(1.0 ~ 10 of the clean bulk drug of described Ka Gelie and the weight of described water), preferably 1:(1.0 ~ 5.0).
In step 3, the temperature of described crystallization is 0 ~ 40 ℃, this scope has comprised any concrete point value belonging to wherein, can be for example 0 ℃, 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ or 40 ℃, also comprise the numerical range that any two point values in these concrete point values form, preferably 10 ~ 30 ℃.
Compared with prior art, the present invention has following beneficial effect: the character that can produce different spectrum according to specific polymorphic, it is the clean crystal formation of Ka Gelie that the present invention detects product prepared by preparation method of the present invention by powder x-ray diffraction, and has measured the fusing point of crystal by poor formula scanning calorimetry (TGA-DSC).The present invention is by the strict consumption of controlling solvent in recrystallization temperature, time and process, yield and the purity of the clean crystal formation of Ka Gelie are improved widely, productive rate is the highest can reach 85%, purity is up to 99.9%, the method is easy and simple to handle simultaneously, cost is low, is suitable for the clean suitability for industrialized production of Ka Gelie of high purity, high yield, has very high economic benefit.
Accompanying drawing explanation
Fig. 1 is powder X-ray-ray collection of illustrative plates of the clean crystal formation of Ka Gelie prepared of the present invention;
Fig. 2 is the powder TGA-DSC collection of illustrative plates of the clean crystal formation of Ka Gelie prepared of the present invention.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art further to understand the present invention, but not limit in any form the present invention.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1
Card taking lattice are listed as clean bulk drug crude product 10g, add ethyl acetate 20ml, heating for dissolving, add again water 10ml, be cooled to 30 ℃, under stirring, add sherwood oil 20ml, stir 30 minutes, 10 ℃ of stirring and crystallizing 4 h, filter, the 60 ℃ of clean crystal formation product of vacuum-drying get Ka Gelie 8.0g, yield is 80%, purity is 99.6%, as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Card taking lattice are listed as clean bulk drug crude product 10g, add ethyl acetate 30ml, heating for dissolving, add again water 20ml, be cooled to 35 ℃, under stirring, add normal hexane 40ml, stir 45 min, 20 ℃ of stirring and crystallizing 6 h, filter, the clean semihydrate medicinal crystal-form of get Ka Gelie product 7.5g after 55 ℃ of vacuum are dry, yield is 75%, purity is 99.9%, as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Embodiment 3
Card taking lattice are listed as clean bulk drug crude product 10g, add ethyl acetate 50ml, heating for dissolving, add again water 10ml, be cooled to 40 ℃, under stirring, add methyl tertiary butyl ether 50ml, stir 60 min, 30 ℃ of stirring and crystallizing 10 h, filter, the clean crystal formation product of get Ka Gelie 6.8g after 50 ℃ of vacuum are dry, yield is 68%, purity is 99.3%, as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Embodiment 4
Card taking lattice are listed as clean bulk drug crude product 10g, add acetone 30ml, heating for dissolving, add again water 10ml, be cooled to 30 ℃, stir 30 min, add crystal seed, 15 ℃ of stirring and crystallizing 6 h, filter the clean crystal formation product of get Ka Gelie 8.2g after 45 ℃ of vacuum-dryings, yield scope 82%, purity is 99.5%, and as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Embodiment 5
Card taking lattice are listed as clean bulk drug crude product 10g, add acetone 40ml, heating for dissolving, add again water 20ml, be cooled to 35 ℃, stir 45 min, add crystal seed, 25 ℃ of stirring and crystallizing 8 h, filter the clean crystal formation product of get Ka Gelie 8.5g after 40 ℃ of vacuum-dryings, yield scope 85%, purity is 99.9%, and as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Embodiment 6
Card taking lattice are listed as clean bulk drug crude product 10g, add acetone 50ml, heating for dissolving, add again water 10ml, be cooled to 40 ℃, stir 60 min, add crystal seed, 30 ℃ of stirring and crystallizing 10 h, filter the clean crystal formation product of get Ka Gelie 7.1g after 60 ℃ of vacuum, yield scope 71%, purity is 99.4%, and as shown in Figure 1, its TGA-DSC collection of illustrative plates as shown in Figure 2 for its X-ray collection of illustrative plates.
Above specific embodiments of the invention are described.It will be appreciated that, the present invention is not limited to above-mentioned specific implementations, and those skilled in the art can make various distortion or modification within the scope of the claims, and this does not affect flesh and blood of the present invention.
Claims (9)
1. the preparation method of the clean semihydrate medicinal crystal-form of Yi Zhong Ka Gelie, is characterized in that, comprises the steps:
Step 1, card taking lattice are listed as clean bulk drug, add organic solvent, and then heating for dissolving adds and is water-cooled to 30 ~ 40 ℃;
Step 2 adds organic solvent or after 30 ~ 60 minutes, adds crystal seed in stirring under the condition stirring;
Step 3, under 10 ~ 30 ℃ of conditions of temperature, stirs 4 ~ 10 hours crystallizatioies, filters, and collects the crystallization of separating out, 40 ~ 60 ℃ of vacuum-dryings, the i.e. clean semihydrate medicinal crystal-form of get Ka Gelie.
2. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 1, is characterized in that, in step 1, described organic solvent is selected from least one in ethyl acetate, acetone, methyl alcohol, ethanol and toluene.
3. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 1, is characterized in that, in step 2, described organic solvent is selected from least one in ether, methyl tertiary butyl ether, sherwood oil, normal hexane and hexanaphthene.
4. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 1, it is characterized in that the clean bulk drug of Ka Gelie described in step 1: organic solvent described in step 1: the ratio of the consumption of organic solvent described in step 2 is 1 weight part: (1 ~ 10) parts by volume: (1 ~ 10) parts by volume.
5. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 4, it is characterized in that the clean bulk drug of Ka Gelie described in step 1: organic solvent described in step 1: the ratio of the consumption of organic solvent described in step 2 is 1 weight part: (2 ~ 5) parts by volume: (2 ~ 5) parts by volume.
6. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 1, is characterized in that, in step 1, the clean bulk drug of described Ka Gelie is 1:(1.0 ~ 10 with the ratio of the weight of described water).
7. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 6, is characterized in that, the clean bulk drug of described Ka Gelie is 1:(1 ~ 5 with the ratio of the weight of described water).
8. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 1, is characterized in that, in step 3, the temperature of described crystallization is 0 ~ 40 ℃.
9. the preparation method of the clean semihydrate medicinal crystal-form of a kind of Ka Gelie according to claim 8, is characterized in that, the temperature of described crystallization is 10 ~ 30 ℃.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN105541818A (en) * | 2016-03-04 | 2016-05-04 | 浙江华海药业股份有限公司 | Novel crystal form of canagliflozin hydrate and preparation method of novel crystal form |
| WO2016101432A1 (en) * | 2014-12-25 | 2016-06-30 | 重庆医药工业研究院有限责任公司 | Crystal form i of canagliflozin and preparation method thereof |
| CN106279134A (en) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技（武汉）有限公司 | Canagliflozin monocrystalline and its production and use |
| CN108368096A (en) * | 2015-12-21 | 2018-08-03 | 詹森药业有限公司 | Crystallization procedure for obtaining canagliflozin hemi-hydrate crystalline |
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| CN101801371A (en) * | 2007-09-10 | 2010-08-11 | 詹森药业有限公司 | The preparation method of the chemical compound of useful as inhibitors of sglt |
| WO2013064909A2 (en) * | 2011-10-31 | 2013-05-10 | Scinopharm Taiwan, Ltd. | Crystalline and non-crystalline forms of sglt2 inhibitors |
| CN103641822A (en) * | 2013-10-21 | 2014-03-19 | 江苏奥赛康药业股份有限公司 | Canagliflozin compound and pharmaceutical composition thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016101432A1 (en) * | 2014-12-25 | 2016-06-30 | 重庆医药工业研究院有限责任公司 | Crystal form i of canagliflozin and preparation method thereof |
| JP2018500368A (en) * | 2014-12-25 | 2018-01-11 | 重慶医薬工業研究院有限責任公司 | Canagliflozin crystal form I and process for producing the same |
| AU2015372234B2 (en) * | 2014-12-25 | 2019-02-14 | Chongqing Pharmaceutical Industrial Research Institute Co., Ltd | Crystal form l of Canagliflozin and preparation method thereof |
| CN104744449A (en) * | 2015-03-21 | 2015-07-01 | 北京工业大学 | Preparation method of canagliflozin hemihydrate and monocrystal thereof |
| CN106279134A (en) * | 2015-06-23 | 2017-01-04 | 中美华世通生物医药科技（武汉）有限公司 | Canagliflozin monocrystalline and its production and use |
| CN108368096A (en) * | 2015-12-21 | 2018-08-03 | 詹森药业有限公司 | Crystallization procedure for obtaining canagliflozin hemi-hydrate crystalline |
| CN108368096B (en) * | 2015-12-21 | 2021-12-10 | 詹森药业有限公司 | Crystallization procedure for obtaining canagliflozin hemihydrate crystals |
| CN105541818A (en) * | 2016-03-04 | 2016-05-04 | 浙江华海药业股份有限公司 | Novel crystal form of canagliflozin hydrate and preparation method of novel crystal form |
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