CN104311516A - Benzbromarone of crystal form B, and its preparation method - Google Patents
Benzbromarone of crystal form B, and its preparation method Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention relates to benzbromarone of crystal form B applied in the field of chemical pharmacy, and its preparation method. In the X-ray powder diffraction pattern represented by 2theta angles of the benzbromarone of crystal form B, the error range of the 2theta angles is +/-0.2, and the benzbromarone of crystal form B has a basic X-ray powder diffraction pattern; and in the differential scanning calorimetry pattern of the benzbromarone of crystal form B, a maximum endothermic peak exists when the heating speed is 10DEG C/min, and the maximum endothermic peak begins at 150.54DEG C, reaches the top at 151.62DEG C and ends at 153.82DEG C, the melting point is 151.66DEG C; when 10ml of trichloromethane is added to 1.0g of the benzbromarone of crystal form B at 25DEG C, a very small amount of the benzbromarone of crystal form B is not dissolved, and the obtained solution is not clear; and 25ml of N,N-dimethyl formamide is added to the 1.25g of benzbromarone of crystal form B, the benzbromarone of crystal form B is complete dissolved, and the obtained solution is clear. The benzbromarone of crystal form B has good stability, and the preparation method has the advantages of simplicity, low cost, simple post-treatment, high product purity and few relevant substances.
Description
Technical field
The present invention relates to a kind of benzbromarone crystal form B in chemical pharmacy field and preparation method thereof.
Background technology
Benzbromarone, has another name called benzbromarone, narcaricin, TONGFENGNING etc.This product is benzofuran derivative, has and suppresses uriniferous tubules thus to reduce uric acid concentration in blood to the resorption of uric acid.Oral easy absorption, its meta-bolites is for there being acting type, and in latter 24 hours blood of taking medicine, uric acid is 66.5% before taking medicine.Be used for the treatment of gout.
Benzbromarone is in 1971 in Germany's listing, and in August, 1978 obtains license with the trade(brand)name of Urinorm, starts selling tablet from April, 1979.Benzbromarone just occupies the position of antigout class medicine hospital administration first place after entering China from 2000, and the market share of benzbromarone is still in rising trend at present, and its market potential is difficult to estimate.
Find that existing patent majority is the protection of preparation method to benzbromarone synthesis or different dosage form and purposes by Chinese patent retrieval, find no the report of pass benzbromarone crystal formation and existing medicament forms poor stability, its related substances are high, crystallization purifications industrial applications is poor through searching document and domestic and international patent.Therefore, so stable benzbromarone form how can be prepared, and the crystallization purifications industrial applications new problem that to be well current assistant officer to be solved.
Summary of the invention
The object of the present invention is to provide a kind of benzbromarone crystal form B and preparation method thereof, this invention stability of crystal form is good, preparation method is simple, cost is low, aftertreatment is simple, obtained product purity is high and related substance is few.
The object of the present invention is achieved like this: a kind of benzbromarone crystal form B, described benzbromarone crystal form B, in the X-ray powder diffraction represented with 2 θ angles, be included in 22.57,25.27,26.05,20.74,16.50,12.04,20.23,23.78,27.08 and 21.09 and there is main diffraction peak, limit of error ± 0.2 of described 2 θ angles; Described benzbromarone crystal form B, in the X-ray powder diffraction represented with 2 θ angles, has following diffraction peak:
Described benzbromarone crystal form B has X-ray powder diffraction substantially as shown in Figure 2; Described benzbromarone crystal form B in infrared absorption spectrum, 3082,2988,2966,2930,2872,1616,1583,1570,1542,1477,1453,1431,1396,1313,1296,1280,1229,1173,1136,1099,1051,1012,989,945,908,754,746cm-1 place has absorption peak; A maximum endotherm(ic)peak is there is when heat-up rate is per minute 10 DEG C in described benzbromarone crystal form B in Differential Scanning Calorimetry, peak starting point: 150.54 DEG C, peak value: 151.62 DEG C, peak terminating point: 153.82 DEG C, benzbromarone crystal form B melting point values: 151.66 DEG C; Under 25 DEG C of conditions, get described benzbromarone crystal form B material 1.0g, add trichloromethane 10ml, solid is slightly insoluble, and solution is not clarified; And get benzbromarone crystal form B material 1.25g, add DMF 25ml, solid all dissolves, and solution is clarified; Be dissolved in acetone by benzbromarone raw material, the crystallization that then adds water obtains described benzbromarone crystal form B; The quality of described benzbromarone raw material and the volume ratio of acetone are 1:9-15, and the quality of described benzbromarone raw material and the volume ratio of water are 1:13-25, and the unit of described quality is gram, and the unit of described volume is milliliter; The described benzbromarone raw material temperature be dissolved in acetone is 20-30 DEG C, and described crystallization is for leaving standstill crystallization, and the temperature of described standing crystallization is 0-20 DEG C, and the time of described standing crystallization is no less than 2 hours; Get benzbromarone raw material 7.2g to be dissolved in completely in the acetone solvent of 65ml under temperature is 22 DEG C of conditions, then add water 93.6ml, have solid to separate out gradually, 5 DEG C of standing crystallizatioies 10 hours, filter, with a small amount of cold acetone drip washing, described benzbromarone crystal form B can be obtained.
Main points of the present invention are benzbromarone crystal form B and preparation method thereof.Its pharmacy principle is: (1) obtains described benzbromarone crystal form B by crystallization from acetone-water solvent system, and purity is high, its related substances is few.(2) benzbromarone crystal form B of the present invention is to all stable under high humidity, illumination and hot conditions.(3) preparation method of the benzbromarone crystal form B described in this invention, simple to operate and mild condition, solvent source are wide, the operating time is short, aftertreatment is simple, cost is low.
A kind of benzbromarone crystal form B and preparation method thereof compared with prior art, the advantage such as have that this stability of crystal form is good, this preparation method is simple, cost is low, aftertreatment is simple, the high and related substance of obtained product purity is few, will be widely used in chemical pharmacy field.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the present invention is described in detail.
Fig. 1 is the structural formula figure of benzbromarone.
Fig. 2 is the x-ray diffractogram of powder spectrum of benzbromarone crystal form B.
Fig. 3 is the infrared absorpting light spectra of benzbromarone crystal form B.
Fig. 4 is the dsc differential thermal analysis collection of illustrative plates of benzbromarone crystal form B.
Embodiment
Following examples will contribute to understanding of the present invention, but these embodiments are only in order to be illustrated the present invention, and the present invention is not limited to these contents.
Embodiment one
The preparation method of benzbromarone crystal form B sample:
Get benzbromarone raw material 7.2g to be dissolved in completely in the acetone solvent of 65ml under temperature is 22 DEG C of conditions, then add water 93.6ml, have solid to separate out gradually, 5 DEG C of standing crystallizatioies 10 hours, suction filtration, with a small amount of cold acetone drip washing, can obtain the sample of benzbromarone crystal form B.
The x-ray diffractogram of powder spectrum of gained benzbromarone crystal form B as shown in Figure 2.
The infrared absorpting light spectra of gained benzbromarone crystal form B as shown in Figure 3.
The dsc differential thermal analysis collection of illustrative plates of gained benzbromarone crystal form B as shown in Figure 4.
Detection method and the result of dsc differential thermal analysis collection of illustrative plates are as follows:
Benzbromarone (60-240/10),
dt?1.00s，
[1]60.0..240.0℃,10.00K/min，
Synchronously enable,
Integration-173.47mJ,
Normalization method-88.06Jg^-1,
Starting point 150.54 DEG C,
151.62 DEG C, peak,
Terminating point 153.82 DEG C,
DSC purity,
Purity 99.552+/-42.507e-03mol%,
T melting 151.66 DEG C.
Above spectrum data result shows, the crystal formation of the present embodiment gained crystal is benzbromarone crystal form B.
Embodiment two
Get benzbromarone raw material 7.2g to be dissolved in completely in the acetone solvent of 87ml under temperature is 30 DEG C of conditions, then add water 134ml, have solid to separate out gradually, 0 DEG C of standing crystallization 2 hours, suction filtration, with a small amount of cold acetone drip washing, can obtain the sample of benzbromarone crystal form B.
Embodiment three
Get benzbromarone raw material 7.2g to be dissolved in completely in the acetone solvent of 108ml under temperature is 20 DEG C of conditions, then add water 180ml, have solid to separate out gradually, 20 DEG C of standing crystallizatioies 15 hours, suction filtration, with a small amount of cold acetone drip washing, can obtain the sample of benzbromarone crystal form B.
Its its related substances of benzbromarone crystal form B adopting preparation method of the present invention to obtain is far smaller than the standard of European Pharmacopoeia 7.0 editions (1465-1466 page), and the content situation of related substance is in table 1.
Table 1 benzbromarone raw material and crystal form B sample related substance compare with European Pharmacopoeia standard
The benzbromarone crystal form B state solid obtained by this preparation method respectively through 10 days, 20 days, 30 days under the condition of 92.5% humidity, illumination, high temperature 60 DEG C, color and related substance situation as follows:
Table 2 crystal form B sample is in humidity 92.5% condition stability inferior situation
| Time | Outward appearance | Impurity A | Impurity B | Other single impurity | Other impurity and |
| When 0 | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.06％ |
| 10 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.06％ |
| 20 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.07％ |
| 30 days | Off-white color crystalline powder | Do not detect | 0.05％ | 0.03％ | 0.07％ |
Table 3 crystal form B sample is in illumination condition stability inferior situation
| Time | Outward appearance | Impurity A | Impurity B | Other single impurity | Other impurity and |
| When 0 | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.06％ |
| 10 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.06％ |
| 20 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.07％ |
| 30 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.03％ | 0.08％ |
Table 4 crystal form B sample is in high temperature 60 DEG C of condition stability inferior situations
| Time | Outward appearance | Impurity A | Impurity B | Other single impurity | Other impurity and |
| When 0 | Off-white color crystalline powder | Do not detect | 0.04％ | 0.02％ | 0.06％ |
| 10 days | Off-white color crystalline powder | Do not detect | 0.03％ | 0.03％ | 0.06％ |
| 20 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.03％ | 0.06％ |
| 30 days | Off-white color crystalline powder | Do not detect | 0.04％ | 0.04％ | 0.08％ |
From above data, benzbromarone crystal form B solid under the condition of 92.5% humidity, illumination, high temperature 60 DEG C, stability with zero time compare, without considerable change.
Solubility test:
Get the embodiment of the present invention one, two, three gained crystal form B to measure respectively: under 25 DEG C of conditions, benzbromarone crystal form B material 1.0g, add trichloromethane 10ml, solid is slightly insoluble, and solution is not clarified; And synthermal under get benzbromarone crystal form B material 1.25g, add DMF 25ml, solid all dissolves, solution clarify.
Claims (10)
1. a benzbromarone crystal form B, it is characterized in that: described benzbromarone crystal form B, in the X-ray powder diffraction represented with 2 θ angles, be included in 22.57,25.27,26.05,20.74,16.50,12.04,20.23,23.78,27.08 and 21.09 and there is main diffraction peak, limit of error ± 0.2 of described 2 θ angles.
2. a kind of benzbromarone crystal form B according to claim 1, is characterized in that: described benzbromarone crystal form B, in the X-ray powder diffraction represented with 2 θ angles, has following diffraction peak:
。
3. a kind of benzbromarone crystal form B according to claim 1, is characterized in that: described benzbromarone crystal form B has X-ray powder diffraction substantially as shown in Figure 2.
4. a kind of benzbromarone crystal form B according to claim 1, it is characterized in that: described benzbromarone crystal form B in infrared absorption spectrum, 3082,2988,2966,2930,2872,1616,1583,1570,1542,1477,1453,1431,1396,1313,1296,1280,1229,1173,1136,1099,1051,1012,989,945,908,754,746cm-1 place has absorption peak.
5. a kind of benzbromarone crystal form B according to claim 1, it is characterized in that: described benzbromarone crystal form B exists a maximum endotherm(ic)peak when heat-up rate is per minute 10 DEG C in Differential Scanning Calorimetry, peak starting point: 150.54 DEG C, peak value: 151.62 DEG C, peak terminating point: 153.82 DEG C, benzbromarone crystal form B melting point values: 151.66 DEG C.
6. a kind of benzbromarone crystal form B according to claim 1, is characterized in that: under 25 DEG C of conditions, and get described benzbromarone crystal form B material 1.0g, add trichloromethane 10ml, solid is slightly insoluble, and solution is not clarified; And get benzbromarone crystal form B material 1.25g, add DMF 25ml, solid all dissolves, and solution is clarified.
7. a preparation method for benzbromarone crystal form B as claimed in claim 1, is characterized in that: be dissolved in acetone by benzbromarone raw material, the crystallization that then adds water obtains described benzbromarone crystal form B.
8. the preparation method of a kind of benzbromarone crystal form B according to claim 7, it is characterized in that: the quality of described benzbromarone raw material and the volume ratio of acetone are 1:9-15, the quality of described benzbromarone raw material and the volume ratio of water are 1:13-25, the unit of described quality is gram, and the unit of described volume is milliliter.
9. the preparation method of a kind of benzbromarone crystal form B according to claim 7, it is characterized in that: the described benzbromarone raw material temperature be dissolved in acetone is 20-30 DEG C, described crystallization is for leaving standstill crystallization, the temperature of described standing crystallization is 0-20 DEG C, and the time of described standing crystallization is no less than 2 hours.
10. the preparation method of a kind of benzbromarone crystal form B according to claim 7, it is characterized in that: get benzbromarone raw material 7.2g and be dissolved in completely in the acetone solvent of 65ml under temperature is 22 DEG C of conditions, then water 93.6ml is added, solid is had to separate out gradually, 5 DEG C of standing crystallizatioies 10 hours, filter, with a small amount of cold acetone drip washing, described benzbromarone crystal form B can be obtained.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020118113A1 (en) * | 2018-12-06 | 2020-06-11 | Arthrosi Therapeutics, Inc. | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
| US11236058B2 (en) | 2016-07-18 | 2022-02-01 | Arthrosi Therapeutics, Inc. | Compounds, compositions and methods for treating or preventing a symptom associated with gout or hyperuricemia |
| WO2023098872A1 (en) * | 2021-12-02 | 2023-06-08 | Arthrosi Therapeutics, Inc. | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11236058B2 (en) | 2016-07-18 | 2022-02-01 | Arthrosi Therapeutics, Inc. | Compounds, compositions and methods for treating or preventing a symptom associated with gout or hyperuricemia |
| WO2020118113A1 (en) * | 2018-12-06 | 2020-06-11 | Arthrosi Therapeutics, Inc. | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
| CN113226302A (en) * | 2018-12-06 | 2021-08-06 | 安索治疗公司 | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
| JP2022511800A (en) * | 2018-12-06 | 2022-02-01 | アースローシ セラピューティクス，インク． | Crystalline form of compound for treating or preventing gout or hyperuricemia |
| CN113226302B (en) * | 2018-12-06 | 2023-08-18 | 广州瑞安博医药科技有限公司 | Crystalline forms of a compound for the treatment or prophylaxis of gout or hyperuricemia |
| TWI828817B (en) * | 2018-12-06 | 2024-01-11 | 大陸商廣州瑞安博醫藥科技有限公司 | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
| WO2023098872A1 (en) * | 2021-12-02 | 2023-06-08 | Arthrosi Therapeutics, Inc. | Crystalline forms of a compound for treating or preventing gout or hyperuricemia |
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