CN104311516B - 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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- CN104311516B CN104311516B CN201410473218.9A CN201410473218A CN104311516B CN 104311516 B CN104311516 B CN 104311516B CN 201410473218 A CN201410473218 A CN 201410473218A CN 104311516 B CN104311516 B CN 104311516B
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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
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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 formation B in chemical pharmacy field and preparation method thereof.
Background technology
Benzbromarone, has another name called benzbromarone, narcaricin, TONGFENGNING etc..This product is benzofuran derivatives, has suppression kidney
Tubule to the resorption of uric acid thus reduce uric acid concentration in blood.Oral easily absorption, its metabolite, for there being acting type, is taken medicine
In latter 24 hours blood, uric acid is 66.5% before taking medicine.For treating gout.
Benzbromarone listed in Germany in 1971, and in August, 1978 obtains license, from 1979 with the trade name of Urinorm
April in year starts selling tablet.Benzbromarone just occupies gout class medicine hospital administration first after within 2000, entering China
The position of name, and, the market share of benzbromarone is the most in rising trend, and its market potential is difficult to estimate.
Find that existing patent majority is the preparation method to benzbromarone synthesis or different dosage form by Chinese patent retrieval
With the protection of purposes, find no through searching document and domestic and international patent and close the report of benzbromarone crystal formation and existing medicine shape
Formula poor stability, relevant content of material height, crystallization purifications industrial applications are poor.Therefore, so how can be prepared into
To stable benzbromarone form, and crystallization purifications industrial applications is well the new problem that current assistant officer is to be solved.
Summary of the invention
It is an object of the invention to provide a kind of benzbromarone crystal formation B and preparation method thereof, this invention stability of crystal form is good,
Preparation method is simple, low cost, post processing is simple, the product purity for preparing is high and has related substance few.
The object of the present invention is achieved like this: a kind of benzbromarone crystal formation B, described benzbromarone crystal formation B, with 2 θ
In the X-ray powder diffraction spectrum that angle represents, be included in 22.57,25.27,26.05,20.74,16.50,12.04,
20.23,23.78,27.08 and 21.09 have main diffraction maximum, range of error ± 0.2 of described 2 θ angles；Described benzbromarone
Crystal formation B, in the X-ray powder diffraction spectrum represented with 2 θ angles, has a following diffraction maximum:
Described benzbromarone crystal formation B has X-ray powder diffraction spectrum the most as shown in Figure 2；Described benzene bromine horse
Grand crystal formation B in infrared absorption spectroscopy, 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、
There is at 746cm-1 absworption peak；Described benzbromarone crystal formation B is per minute when programming rate in Differential Scanning Calorimetry
A maximum endothermic peak, peak starting point: 150.54 DEG C, peak value: 151.62 DEG C, peak terminating point: 153.82 DEG C, benzene is there is when 10 DEG C
Bromine horse grand crystal formation B melting point values: 151.66 DEG C；Under the conditions of 25 DEG C, take described benzbromarone crystal formation B substance 1.0g, add chloroform
10ml, solid is the most insoluble, and solution is not clarified；And take benzbromarone crystal formation B substance 1.25g, add DMF
25ml, solid all dissolves, and solution is clarified；Being dissolved in acetone by benzbromarone raw material, the crystallize that then adds water obtains described benzene
Bromine horse grand crystal formation B；The quality of described benzbromarone raw material and the volume ratio of acetone are 1:9-15, the matter of described benzbromarone raw material
Amount 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；Described benzbromarone
The temperature that raw material is dissolved in acetone is 20-30 DEG C, and described crystallize is for standing crystallize, and the temperature of described standing crystallize is 0-20 DEG C,
The time of described standing crystallize is no less than 2 hours；Take benzbromarone raw material 7.2g to be dissolved completely under the conditions of temperature is 22 DEG C
In the acetone solvent of 65ml, being subsequently adding water 93.6ml, gradually have solid to separate out, 5 DEG C stand crystallize 10 hours, filter, with few
Amount cold acetone drip washing, can obtain described benzbromarone crystal formation B.
The present invention is characterized by benzbromarone crystal formation B and preparation method thereof.Its pharmacy principle is: (1) by from acetone-
In aqueous solvent, crystallization obtains described benzbromarone crystal formation B, and high, the relevant content of material of purity is few.(2) the benzene bromine of the present invention
Horse grand crystal formation B is to the most stable under high humidity, illumination and hot conditions.(3) the preparation side of the benzbromarone crystal formation B described in this invention
Method, simple to operate and mild condition, solvent source is wide, the operating time is short, post processing is simple, low cost.
A kind of benzbromarone crystal formation B and preparation method thereof compared with prior art, has that this stability of crystal form is good, this prepares
Method is simple, low cost, post processing is simple, the product purity for preparing is high and has the advantages such as related substance is few, will be widely applied
In chemical pharmacy field.
Accompanying drawing explanation
Below in conjunction with the accompanying drawings and embodiment 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 formation B.
Fig. 3 is the infrared absorpting light spectra of benzbromarone crystal formation B.
Fig. 4 is the differential scanning calorimetry differential thermal analysis collection of illustrative plates of benzbromarone crystal formation B.
Detailed description of the invention
Following example will assist in the understanding to the present invention, but these embodiments are only for being illustrated the present invention,
The present invention is not limited to these contents.
Embodiment one
The preparation method of benzbromarone crystal formation B sample:
Take benzbromarone raw material 7.2g to be dissolved completely in the acetone solvent of 65ml under the conditions of temperature is 22 DEG C, then add
Entering water 93.6ml, gradually have solid to separate out, 5 DEG C stand crystallize 10 hours, sucking filtration, with a small amount of cold acetone drip washing, can obtain benzene
The sample of bromine horse grand crystal formation B.
The x-ray diffractogram of powder of gained benzbromarone crystal formation B is composed as shown in Figure 2.
The infrared absorpting light spectra of gained benzbromarone crystal formation B is as shown in Figure 3.
The differential scanning calorimetry differential thermal analysis collection of illustrative plates of gained benzbromarone crystal formation B is as shown in Figure 4.
Detection method and the result of differential scanning calorimetry differential thermal analysis collection of illustrative plates are as follows:
Benzbromarone (60-240/10),
Dt 1.00s,
[1] 60.0..240.0 DEG C, 10.00K/min,
Synchronization enables,
Integration-173.47mJ,
Normalization-88.06Jg^-1,
Starting point 150.54 DEG C,
151.62 DEG C of peak,
Terminating point 153.82 DEG C,
DSC purity,
Purity 99.552+/-42.507e-03mol%,
T melts 151.66 DEG C.
Above spectrum data result shows, the crystal formation of the present embodiment gained crystal is benzbromarone crystal formation B.
Embodiment two
Take benzbromarone raw material 7.2g to be dissolved completely in the acetone solvent of 87ml under the conditions of temperature is 30 DEG C, then add
Entering water 134ml, gradually have solid to separate out, 0 DEG C stands crystallize 2 hours, sucking filtration, with a small amount of cold acetone drip washing, can obtain benzene bromine
The sample of horse grand crystal formation B.
Embodiment three
Take benzbromarone raw material 7.2g to be dissolved completely in the acetone solvent of 108ml under the conditions of temperature is 20 DEG C, then
Adding water 180ml, gradually have solid to separate out, 20 DEG C stand crystallize 15 hours, sucking filtration, with a small amount of cold acetone drip washing, can obtain
The sample of benzbromarone crystal formation B.
Its relevant content of material of benzbromarone crystal formation B obtained by the preparation method of the present invention is used to be far smaller than Europe medicine
The standard of allusion quotation 7.0 editions (1465-1466 pages), has the content situation of related substance to be shown in Table 1.
Table 1 benzbromarone raw material and crystal formation B sample have the comparison of related substance and European Pharmacopoeia standard
The benzbromarone crystal formation B state solid obtained by this preparation method respectively through 10 days, 20 days, 30 days 92.5%
Under conditions of humidity, illumination, high temperature 60 DEG C, color and have related substance situation as follows:
Table 2 crystal formation B sample steadiness under the conditions of humidity 92.5%
| 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 formation 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 formation B sample steadiness under the conditions of high temperature 60 DEG C
| 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 data above, benzbromarone crystal formation B solid is under conditions of 92.5% humidity, illumination, high temperature 60 DEG C, surely
Qualitative with zero time compare, without significant change.
Solubility test:
Take the embodiment of the present invention one, two, three gained crystal formation B to be measured respectively: under the conditions of 25 DEG C, benzbromarone crystal formation B
Material 1.0g, adds chloroform 10ml, and solid is the most insoluble, and solution is not clarified；And under synthermal, take benzbromarone crystal formation B substance
1.25g, adds DMF 25ml, and solid all dissolves, and solution is clarified.
Claims (9)
1. the preparation method of a benzbromarone crystal formation B, it is characterised in that: benzbromarone raw material is dissolved in acetone, then adds
Elutriation crystalline substance obtains described benzbromarone crystal formation B；Described benzbromarone crystal formation B, at the X-ray powder represented with 2 θ angles
In diffracting spectrum, it is included in 22.57,25.27,26.05,20.74,16.50,12.04,20.23,23.78,27.08 and 21.09
There is main diffraction maximum, range of error ± 0.2 of described 2 θ angles.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: described benzene bromine horse
Grand crystal formation B, in the X-ray powder diffraction spectrum represented with 2 θ angles, has a following diffraction maximum:
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: described benzene bromine horse
Grand crystal formation B has X-ray powder diffraction spectrum the most as shown in Figure 2.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: described benzene bromine horse
Grand crystal formation B in infrared absorption spectroscopy, 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-1Place has absworption peak.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: described benzene bromine horse
There is a maximum endothermic peak in grand crystal formation B in Differential Scanning Calorimetry, peak initiates when programming rate is 10 DEG C per minute
Point: 150.54 DEG C, peak value: 151.62 DEG C, peak terminating point: 153.82 DEG C, benzbromarone crystal formation B melting point values: 151.66 DEG C.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: under the conditions of 25 DEG C, take
Described benzbromarone crystal formation B substance 1.0g, adds chloroform 10ml, and solid is the most insoluble, and solution is not clarified；And take benzbromarone
Crystal formation B substance 1.25g, adds DMF 25ml, and solid all dissolves, and solution is clarified.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: described benzbromarone
The quality of 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,
The unit of described quality is gram, and the unit of described volume is milliliter.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 7, it is characterised in that: described benzbromarone
The temperature that raw material is dissolved in acetone is 20-30 DEG C, and described crystallize is for standing crystallize, and the temperature of described standing crystallize is 0-20 DEG C,
The time of described standing crystallize is no less than 2 hours.
The preparation method of a kind of benzbromarone crystal formation B the most according to claim 1, it is characterised in that: take benzbromarone former
Material 7.2g is dissolved completely in the acetone solvent of 65ml under the conditions of temperature is 22 DEG C, is subsequently adding water 93.6ml, gradually has solid
Body separates out, and 5 DEG C stand crystallize 10 hours, filter, with a small amount of cold acetone drip washing, can obtain described benzbromarone crystal formation B.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP3484862B1 (en) | 2016-07-18 | 2021-09-01 | Arthrosi Therapeutics, Inc. | Compounds, compositions and methods for treating or preventing a symptom associated with gout or hyperuricemia |
| EA202191545A1 (en) * | 2018-12-06 | 2021-10-28 | Артроси Терапьютикс, Инк. | CRYSTALLINE FORM OF COMPOUNDS FOR TREATMENT OR PREVENTION OF GUT 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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2014
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| DE3221579A1 (en) * | 1982-06-08 | 1983-12-22 | Eckert, Theodor, Prof. Dr., 4400 Münster | Solubilisation of active substances, which are sparingly soluble in water, in aqueous solution using a mixture of cholinephosphoric acid glycerol diester (choline-lecithin) and sodium deoxycholate as solubiliser, and the therapeutic use of the aqueous solutions obtained thereby |
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