CN101824007A - New crystal form M of Febuxostat and preparation method thereof - Google Patents
New crystal form M of Febuxostat and preparation method thereof Download PDFInfo
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- CN101824007A CN101824007A CN201010157969A CN201010157969A CN101824007A CN 101824007 A CN101824007 A CN 101824007A CN 201010157969 A CN201010157969 A CN 201010157969A CN 201010157969 A CN201010157969 A CN 201010157969A CN 101824007 A CN101824007 A CN 101824007A
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Abstract
The invention discloses a new crystal form M of Febuxostat and a preparation method thereof. The Febuxostat is common name of 2-[3-cyano-4-isobutoxyphenyl]-4-methylthiazol-5-carboxylic acid. The X-ray powder diffraction of a crystal of the new crystal form M of the invention is characterized in that: when a reflection angle is 2theta, absorption peaks exist at positions of 8.54+/-0.3, 9.91+/-0.3, 12.09+/-0.3, 13.15+/-0.3, 17.57+/-0.3, 19.61+/-0.3, 24.28+/-0.3, and 26.22+/-0.3. In a method for recrystallizing the crystal form M, an acetone/methanol mixed solvent with low toxicity is used as a recrystallization solvent, so the method has high safety and convenient operation. The new form M provided by the invention has low hygroscopicity, high stability, and difficult deterioration under a high humidity environment, and is suitable to be prepared into a stable medicinal preparation; and because of high water solubility of the new crystal form M, the prepared medicinal preparation can be easy to absorb by patients.
Description
Technical field
The present invention relates to new crystal of Febuxostat (Febuxostat) and preparation method thereof.
Background technology
Febuxostat (Febuxostat) is the 2-[3-cyano-4-isobutoxy phenyl]-common name of 4-methylthiazol-5-formic acid; Corresponding English name is: 2-[3-Cyano-4-isobutoxyphenyl]-4-methylthiazole-5-carboxylic acid or 2-[3-Cyano-4-(2-methylpropoxy) phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid; Its structural formula is:
Febuxostat is mainly used in the treatment of hyperuricemia clinically as xanthine oxidase inhibitor of new generation.
CN1275126 discloses 5 kinds of crystal form As, B, C, D, G and a kind of amorphousness of Febuxostat, and wherein the A crystalline substance is wherein relative stable crystal formation, and the D crystalline substance is a methylate, and the G crystalline substance is a hydrate; This patent substantially all is to adopt the solvent system of methanol or isopropanol to carry out crystallization, and can carry out the crystal formation conversion according to different drying meanss.
CN101139325A has put down in writing crystal formation I and crystal form II, and wherein crystal formation I adopts re-crystallizing in ethyl acetate to obtain; Crystal form II is to heat mixed dissolution by Febuxostat and ethanol, sodium hydroxide solution, and then acidifying, and crystallization forms.
CN1970547 has announced H, I, J totally 3 kinds of crystal formations, and the crystal formation of this patent all is that the organic solvent recrystallization by cyano-containings such as acetonitrile, propionitrile forms.
CN100546985C has announced a kind of crystallite of Febuxostat, and this crystallite forms by re-crystallizing in ethyl acetate.
CN101386605A has announced the K crystal formation, and this crystal formation adopts 1, and 4-dioxane recrystallization forms.
Summary of the invention
The invention provides a kind of new crystal of Febuxostat, described new crystal preparation method is simple, and solvent is inexpensive, and toxicity is little, the mild condition of recrystallization; The new crystal of preparation gained, stable in properties, but standing storage never degenerate, and water-soluble better, make the pharmaceutical preparation that makes can be easy to be absorbed by the patient.
In order to achieve the above object, the present invention also provides a kind of new crystal (called after crystal form M) of Febuxostat, described Febuxostat crystalline X-ray powder diffraction with crystal form M shows as when reflection angle is 2 θ, 8.54 ± 0.3, and 9.91 ± 0.3,12.09 ± 0.3,13.15 ± 0.3,17.57 ± 0.3,19.61 ± 0.3,24.28 ± 0.3,26.22 ± 0.3 (± 0.3 is the acceptable limit of error of 2 θ values) locate to have absorption peak.
The present invention also provides a kind of preparation method of new crystal form M of Febuxostat, this method comprises following concrete steps: add the acetone/methanol mixed solvent in the container that fills the Febuxostat powder, stir, heating, after treating to dissolve fully, naturally lower the temperature, obtain the M crystal formation crystal of described Febuxostat.
The mass volume ratio (grams per milliliter) of described Febuxostat powder and acetone/methanol mixed solvent is 1: 5～1: 100.
Further, to comprise the volume ratio of acetone and methyl alcohol be 1: 0.5～1: 2 to described acetone/methanol mixed solvent.
Described recrystallization temperature is 5～40 ℃.
Among the present invention, the mensuration of 2 θ values is used CuK α light source.
New crystal form M provided by the invention all has good stability, but is suitable for preparing various stabilised pharmaceutical and prolonged preservation, and water-soluble better, makes the pharmaceutical preparation that makes can be easy to be absorbed by the patient.
The preparation method of new crystal form M provided by the invention, mild condition, simple to operate, the yield height, described recrystallization solvent is cheap and easy to get, and cost is low, pollutes little.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrum of the new crystal form M of Febuxostat of the present invention.
Embodiment
Below in conjunction with embodiment the preparation method's of the new crystal form M of the Febuxostat of this explanation technical scheme is described further.
The 2g Febuxostat is joined in the 50ml round-bottomed flask, and (acetone: methyl alcohol=1: 1), reflux slowly is cooled to 15 ℃ to dissolving fully, and stirring and crystallizing obtains 1.8g Febuxostat crystal to add 10ml acetone/methanol solvent.The gained crystal is carried out the test of X-ray powdery diffractometry, and the gained spectrogram as shown in Figure 1.
The 2g Febuxostat is joined in the 500ml round-bottomed flask, and (acetone: methyl alcohol=1: 2), reflux slowly is cooled to 5 ℃ to dissolving fully, and stirring and crystallizing obtains 1.5g Febuxostat crystal to add 200ml acetone/methanol solvent.The gained crystal is carried out the test of X-ray powdery diffractometry, and the gained spectrogram as shown in Figure 1.
Embodiment 3
The 2g Febuxostat is joined in the 250ml round-bottomed flask, and (acetone: methyl alcohol=1: 1.5), reflux slowly is cooled to 25 ℃ to dissolving fully, and stirring and crystallizing obtains 1.6g Febuxostat crystal to add 100ml acetone/methanol solvent.The gained crystal is carried out the test of X-ray powdery diffractometry, and the gained spectrogram as shown in Figure 1.
Embodiment 4
The 2g Febuxostat is joined in the 100ml round-bottomed flask, and (acetone: methyl alcohol=1: 0.5), reflux slowly is cooled to 40 ℃ to dissolving fully, and stirring and crystallizing obtains 1.7g Febuxostat crystal to add 50ml acetone/methanol solvent.The gained crystal is carried out the test of X-ray powdery diffractometry, and the gained spectrogram as shown in Figure 1.
Although content of the present invention has been done detailed introduction by above preferred embodiment, will be appreciated that above-mentioned description should not be considered to limitation of the present invention.After those skilled in the art have read foregoing, for multiple modification of the present invention with to substitute all will be conspicuous.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (5)
1. the crystal form M of a Febuxostat, it is characterized in that, the crystalline X-ray powder diffraction figure of described crystal form M when reflection angle is 2 θ, 8.54 ± 0.3,9.91 ± 0.3,12.09 ± 0.3,13.15 ± 0.3,17.57 ± 0.3,19.61 ± 0.3,24.28 ± 0.3,26.22 ± 0.3 places have absorption peak.
2. the preparation method of the crystal form M of Febuxostat as claimed in claim 1, it is characterized in that, this method comprises following concrete steps: add the acetone/methanol mixed solvent in the container that fills the Febuxostat powder, stir, heating, after treating to dissolve fully, lower the temperature naturally, obtain the M crystal formation crystal of described Febuxostat.
3. the preparation method of the crystal form M of Febuxostat as claimed in claim 2 is characterized in that, the mass volume ratio (grams per milliliter) of described Febuxostat and acetone/methanol mixed solvent is 1: 5～1: 100.
4. the preparation method of the crystal form M of Febuxostat as claimed in claim 2 is characterized in that, the volume ratio that described acetone/methanol mixed solvent comprises acetone and methyl alcohol is 1: 0.5～1: 2.
5. the preparation method of the crystal form M of Febuxostat as claimed in claim 2 is characterized in that, described recrystallization temperature is 5～40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010157969A CN101824007A (en) | 2010-04-27 | 2010-04-27 | New crystal form M of Febuxostat and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201010157969A CN101824007A (en) | 2010-04-27 | 2010-04-27 | New crystal form M of Febuxostat and preparation method thereof |
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| CN101824007A true CN101824007A (en) | 2010-09-08 |
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| CN201010157969A Pending CN101824007A (en) | 2010-04-27 | 2010-04-27 | New crystal form M of Febuxostat and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058951A (en) * | 2013-01-24 | 2013-04-24 | 吉林化工学院 | Novel febuxostat pharmaceutical co-crystal and preparation method thereof |
| WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
-
2010
- 2010-04-27 CN CN201010157969A patent/CN101824007A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103058951A (en) * | 2013-01-24 | 2013-04-24 | 吉林化工学院 | Novel febuxostat pharmaceutical co-crystal and preparation method thereof |
| WO2016091230A1 (en) | 2014-12-12 | 2016-06-16 | Zentiva, K.S. | Formulations containing a solid solution of febuxostat |
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Application publication date: 20100908 |