CN109651229A - A kind of preparation method of Indobufen crystal form - Google Patents
A kind of preparation method of Indobufen crystal form Download PDFInfo
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- CN109651229A CN109651229A CN201811481531.1A CN201811481531A CN109651229A CN 109651229 A CN109651229 A CN 109651229A CN 201811481531 A CN201811481531 A CN 201811481531A CN 109651229 A CN109651229 A CN 109651229A
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- indobufen
- crystal form
- water
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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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
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- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis fields, specifically disclose a kind of preparation method of Indobufen crystal form, and this method forms specific crystal formation by control cooling rate and growing the grain temperature by the way that Indobufen crude product to be dissolved in polar solvent.This method is easy to operate, safety and environmental protection, at low cost, is suitble to industrialized production；And gained crystal form is not easy to moisture absorption, quality is stablized, it is easily stored.
Description
Technical field
The invention belongs to compound synthesis fields, and in particular to a kind of preparation method of Indobufen crystal form.
Background technique
Indobufen is a kind of raceme mixture researched and developed by Pfizer Inc., by Italian Farmfalia
Carlo Erba S, P, A are succeeded in developing first, and are listed first in August, 1984 in Italian (ICH member state).Indoles cloth
Sweet smell assembles drug as powerful anti-platelet of new generation, and what it can be selected acts on the blood platelet of circulation, blocks thrombosis, suppression
Platelet factor processed discharges and plays antiplatelet aggregative activity, and this inhibition is reversible, and does not change plasma parameters, lossless blood
Platelet function, and the platelet function for making a variation normal is made to restore normal.It can be such that peripheral blood vessel lesion patient and intermittent claudication suffers from
The microcirculation parameter and travel distance of person is obviously improved.Compared with similar drugs, Indobufen inhibits platelet factor, and anti-blood is small
Plate congregational rate is salicylic 2~5 times, compared with there is shorter bleeding time light continuous time.
Patent PL172906B1 discloses two kinds of crystal forms of Indobufen compound, and one of crystal form is logical
Cross the crystal form 1 that isopropanol crystallisation by cooling obtains, fusing point: 183.3-184.9 DEG C, the infrared spectrogram of the crystal form 2965,1725,
1646、1606、1515、1470、1397、1178、741cm-1Place has characteristic peak.It is found through experiment that it is low with crystallinity,
The strong defect of the small, poor fluidity of grain, adhesiveness.
Another crystal form is the crystal form obtained by methanol crystallisation by cooling, fusing point: 180~182 DEG C, the crystal form it is red
Outer spectrogram is in 1723,1707,1690,1646cm-1Place has characteristic peak, and the crystal form is it is found through experiment that it is methanol solvate chemical combination
Object, the defect with solvent toxicity.
Chinese invention patent CN 106397298A discloses pharmaceutical composition and purposes containing Indobufen, by indoles cloth
Fragrant crude product is added in solvent, ultrasonic dissolved clarification, is placed in room temperature~60 DEG C volatilization and is obtained crystal form A；Indobufen crude product is added to pole
Property solvent in, ultrasonic dissolved clarification is added dropwise anti-solvent under stirring condition, 30~60min of time for adding, crystallization, and decompression filters, dry
To crystal form B；The invention also discloses a kind of crystal form C, but stable crystal form is unable to get according to the preparation method of the patent disclosure
C。
Solid chemical belongs to molecular crystal more, and lattice energy difference is smaller, and transformation is easy to happen between different crystal forms.In medicine
In the production preparation process of object or preparation, many factors will affect the transformation for leading to drug crystal forms.Turn brilliant different from crystallization, turns crystalline substance
It is a kind of process of the solid matter from crystal transfer for another crystal form, and crystallizes and can be used for chemical purification, can also uses
It is prepared in crystal-form substances.Influence drug crystal forms, which turn brilliant approach, mainly has grinding to turn crystalline substance, a solvent turns brilliant, temperature turns brilliant, pressure turn
Brilliant, humidity turns crystalline substance, metal ion turns brilliant, melting turns crystalline substance, distillation turns brilliant, turn brilliant, concentration that is suspended turns crystalline substance etc..As crystal form drug object
Matter should have good stability of crystal form, should ensure that and be not susceptible to crystal phenomenon in normal state.
Inventor explores a kind of method for preparing Indobufen crystal form C to stabilization, passes through by repeatedly research in this patent
The study found that the crystal form is not easy to moisture absorption, quality is stablized, and it is easily stored, in production, packaging, storage, do not occur in term of validity
Crystal phenomenon, and preparation and purification process are simple.
Summary of the invention:
In view of the deficiencies of the prior art, the present invention provides the preparation method of Indobufen crystal form C a kind of, this method passes through
Indobufen is dissolved in polar solvent, specific crystal formation is formed by control cooling rate.This method is easy to operate, cost
It is low, and gained crystal form is not easy to moisture absorption, quality is stablized, it is easily stored, it is suitble to industrialized production.Additionally by measuring, former triturate is brilliant
Type, it was demonstrated that crystal form C prepared by the present invention is consistent with former triturate crystal form, this is just to be passed through by preparation prepared by this crystal form in the later period
Conformance Assessment provides prerequisite.
The invention discloses a kind of Indobufen crystal form C, the crystal form C by X-ray powder diffraction, have with 2 θ ° ±
The X-ray powder diffraction figure of 0.2 ° of mark, in following position with characteristic peak: 12.9,16.3,17.3,17.5,19.8,23.9.
Preferably, the crystal form C has by X-ray powder diffraction with 2 θ ° ± 0.2 ° X-ray powder diffractions identified
Figure, in following position with characteristic peak: 8.9,12.9,13.9,16.3,17.3,17.5,19.8,23.9,24.7.
It is furthermore preferred that the crystal form C has X-ray powder diffraction figure substantially as shown in Fig. 1, in following diffraction
There is characteristic peak and its relative intensity at 2 θ of angle:
It is found through experiments that, crystal form C provided by the invention places 6 months crystal forms under 40 DEG C of acceleration environments and do not become
Change, sees attached drawing 2.
The preparation method of Indobufen crystal form C of the present invention, the specific steps are that: polarity is added in Indobufen crude product
In solvent, stirring is heated to reflux to dissolving, after solid is completely dissolved, is cooled down with the speed of 2~15 DEG C/h, temperature is down to
0~30 DEG C, at this temperature growing the grain 2h, filtering, dry Indobufen crystal form C.
95% is no less than containing Indobufen in the Indobufen crude product.
The weight ratio of the Indobufen crude product and solvent is 1:5~15, the preferably weight of Indobufen crude product and solvent
Than for 1:10.It is found through inventor's many experiments, when the weight ratio of Indobufen crude product and solvent is greater than 1:15, product when crystallization
Amount of precipitation is less, extends the crystallization time, and precipitation product, which has no, increased significantly, and product yield reduces, cost relative increase；Indoles cloth
When the weight ratio of fragrant crude product and solvent is less than 1:5, Indobufen crude product cannot be completely dissolved, and can not carry out subsequent cooling crystallization behaviour
Make.
Heretofore described solvent is one of water, methanol, ethyl alcohol, isopropanol, acetone, ethyl acetate, tetrahydrofuran
Or two kinds.It finds through inventor's many experiments, can be obtained using one of above-mentioned solvent or two kinds according to crystallization processes
Stable crystal form C.It is preferred that first alcohol and water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydrofuran and water are with arbitrary volume
The mixed liquor of ratio；The volume ratio of more preferable first alcohol and water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydrofuran and water
For 1:1~8:1；The most preferably volume ratio of first alcohol and water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydrofuran and water
For 3:1.
Heretofore described cooling rate is 2~15 DEG C/h, and cooling rate is excessively slow, and the product cooling crystallization time can be made to prolong
Long, obtained crystal habit is poor；When cooling rate is higher than 15 DEG C/h, cooling rate is too fast, the quick-fried crystalline substance of product crystallization, is formed without fixed
Shape mixes crystal form, and impurity, product quality decline are wrapped up in product crystallization.It is found through inventor's many experiments, cooling rate is only
Have within the scope of 2~15 DEG C/h, stable crystal form C could be formed.Further, cooling rate preferably 4~10 DEG C/h.
Growing the grain temperature is 0~30 DEG C, preferably 0~20 DEG C in the present invention.It is found through inventor's many experiments, growing the grain temperature is low
In 0 DEG C, mixing crystal form easy to form；Growing the grain temperature is excessively high, and portioned product is dissolved in solvent, and product is precipitated and reduces, receives product
Rate reduces.
In conclusion this method is easy to operate the present invention provides the preparation method of Indobufen crystal form C a kind of, safety
Environmental protection, it is at low cost, it is suitble to industrialized production；And gained crystal form is not easy to moisture absorption, quality is stablized, and it is easily stored, it is raw to can be used for preparation
It produces.
Detailed description of the invention
Fig. 1 is the powder x-ray diffraction figure of 1 Indobufen crystal form C of the embodiment of the present invention；
Fig. 2 is the powder X-ray that 1 Indobufen crystal form C of the embodiment of the present invention is placed 6 months under 40 DEG C of acceleration environments
Diffraction pattern；
Fig. 3 is the powder x-ray diffraction figure of 2 Indobufen crystal form C of the embodiment of the present invention；
Fig. 4 is the powder x-ray diffraction figure of 3 Indobufen crystal form C of the embodiment of the present invention；
Fig. 5 is the powder x-ray diffraction figure of 4 Indobufen crystal form C of the embodiment of the present invention；
Fig. 6 is the powder x-ray diffraction figure of 5 Indobufen crystal form C of the embodiment of the present invention；
Specific embodiment:
Below in conjunction with specific embodiment, the invention will be further described, and the following description is only intended to explain the invention,
Protection scope of the present invention is not limited to these examples, it should be understood by those skilled in the art that made by the content of present invention
Equivalent replacement, or be correspondingly improved, it still falls within protection scope of the present invention.
Embodiment 1
Ethanol/water (volume ratio 3/1) in the mixed solvent is added in a certain amount of Indobufen crude product, wherein Indobufen is thick
The weight ratio of product and ethanol/water is 1:10, is warming up to reflux, to dissolving, filtering, filtrate is dropped with the speed of 7 DEG C/h for stirring
Temperature, temperature are down to 20 DEG C, at this temperature growing the grain 2h, and filtering, Washing of Filter Cake, 40~50 DEG C of vacuum drying 4h obtain Indobufen crystalline substance
Type C.The X-ray ray powder diffraction of the crystal has diffracted ray in following d spacing: 8.9,12.9,16.3,17.5,19.8,
23.9、24.7。
Embodiment 2
By a certain amount of Indobufen crude product be added isopropanol/water (volume ratio 1/1) in, wherein Indobufen crude product with it is different
The weight ratio of propanol/water is 1:15, is warming up to reflux, to dissolving, filtering, filtrate is cooled down with the speed of 2 DEG C/h for stirring, temperature
Degree is down to 8 DEG C, and growing the grain 2h, filtering, Washing of Filter Cake, 40~50 DEG C of vacuum drying 4h obtain Indobufen crystal form C at this temperature.It should
The X-ray ray powder diffraction of crystal has diffracted ray in following d spacing: 8.9,12.9,16.3,17.9,23.8,24.0,
24.8。
Embodiment 3
Methanol/water (volume ratio 5/1) in the mixed solvent is added in a certain amount of Indobufen crude product, wherein Indobufen is thick
The weight ratio of product and methanol/water is 1:8, is warming up to reflux, to dissolving, filtering, filtrate is dropped with the speed of 10 DEG C/h for stirring
Temperature, temperature are down to 20 DEG C, at this temperature growing the grain 2h, and filtering, Washing of Filter Cake, 40~50 DEG C of vacuum drying 4h obtain Indobufen crystalline substance
Type C.The X-ray ray powder diffraction of the crystal has diffracted ray in following d spacing: 8.9,12.9,16.3,17.5,19.8,
23.9、24.7。
Embodiment 4
A certain amount of Indobufen crude product is added in acetone/water (volume ratio 8/1), wherein Indobufen crude product and third
Ketone/water weight ratio is 1:5, is warming up to reflux, stirring is to dissolving, and filtering, filtrate is cooled down with the speed of 15 DEG C/h, temperature
13 DEG C are down to, at this temperature growing the grain 2h, filtering, Washing of Filter Cake, 40~50 DEG C of vacuum drying 4h obtain Indobufen crystal form C.It should
The X-ray ray powder diffraction of crystal has diffracted ray in following d spacing: 8.9,12.8,16.3,17.4,19.8,24.0,
24.9。
Embodiment 5
A certain amount of Indobufen crude product is added in tetrahydrofuran, wherein the weight ratio of Indobufen crude product and tetrahydrofuran
For 1:6, it is warming up to reflux, stirring is to dissolving, and filtering, filtrate is cooled down with the speed of 4 DEG C/h, and temperature is down to 10 DEG C, herein
At a temperature of growing the grain 2h, filtering, Washing of Filter Cake, 40~50 DEG C of vacuum drying 4h obtain Indobufen crystal form C.The X-ray of the crystal is penetrated
Line powder diffraction spectrum has diffracted ray in following d spacing: 8.9,13.0,16.3,17.4,17.6,19.9,23.9,24.9.
Claims (9)
1. a kind of preparation method of Indobufen crystal form C, it is characterised in that: specific steps are as follows: Indobufen crude product is added molten
In agent, stirring is heated to reflux to dissolving, after solid is completely dissolved, is cooled down with the cooling rate of 2~15 DEG C/h, is down to 0
~30 DEG C of growing the grain temperature, growing the grain 2h, filtering, dry Indobufen crystal form C.
2. the preparation method of Indobufen crystal form C according to claim 1, it is characterised in that: the crystal form C is penetrated by X-
Line powder diffraction has with 2 θ ° ± 0.2 ° X-ray powder diffraction figures identified, has characteristic peak in following position: 12.9,
16.3、17.3、17.5、19.8、23.9。
3. the preparation method of Indobufen crystal form C according to claim 1, it is characterised in that: the crystal form C is with bottom
It sets with characteristic peak: 8.9,12.9,13.9,16.3,17.3,17.5,19.8,23.9,24.7.
4. the preparation method of Indobufen crystal form C according to claim 1, it is characterised in that: the Indobufen crude product
In be no less than 95% containing Indobufen；The weight ratio of the Indobufen crude product and solvent is 1:5~15；The solvent be water,
One or both of methanol, ethyl alcohol, isopropanol, acetone, ethyl acetate, tetrahydrofuran.
5. the preparation method of Indobufen crystal form C according to claim 4, it is characterised in that: the Indobufen crude product
Weight ratio with solvent is 1:10；The solvent is first alcohol and water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydro furan
It mutters with water with the mixed liquor of arbitrary volume ratio.
6. the preparation method of Indobufen crystal form C according to claim 5, it is characterised in that: the solvent be methanol and
The volume ratio of water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydrofuran and water is the mixed liquor of 1:1~8:1.
7. the preparation method of Indobufen crystal form C according to claim 6, it is characterised in that: the solvent be methanol and
The volume ratio of water, second alcohol and water, isopropyl alcohol and water, acetone and water and tetrahydrofuran and water is the mixed liquor of 3:1.
8. the preparation method of Indobufen crystal form C according to claim 1, it is characterised in that: the cooling rate be 4~
10℃/h；Growing the grain temperature is 0~20 DEG C.
9. the Indobufen crystal form C that claim 1 preparation method obtains.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811481531.1A CN109651229A (en) | 2018-12-05 | 2018-12-05 | A kind of preparation method of Indobufen crystal form |
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| CN201811481531.1A CN109651229A (en) | 2018-12-05 | 2018-12-05 | A kind of preparation method of Indobufen crystal form |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114634440A (en) * | 2020-12-16 | 2022-06-17 | 杭州中美华东制药有限公司 | Indobufen crystal form X and crystal form D and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL172906B1 (en) * | 1993-09-07 | 1997-12-31 | Inst Farmaceutyczny | Method of obtaining indobufene in pharmaceutically advantageous crystalline form |
| CN101270072A (en) * | 2008-02-25 | 2008-09-24 | 北京阜康仁生物制药科技有限公司 | Right-handed indobufen and use for preparing medicament |
| CN101914055A (en) * | 2010-08-02 | 2010-12-15 | 新疆生产建设兵团农六师芳草湖监狱 | Reductive preparation method of imide |
| CN104744339A (en) * | 2013-12-26 | 2015-07-01 | 张云 | Production method of indobufen |
| CN105853364A (en) * | 2016-04-29 | 2016-08-17 | 济南康和医药科技有限公司 | Indobufen solid preparation and preparing method |
| CN106397298A (en) * | 2016-08-11 | 2017-02-15 | 杭州中美华东制药有限公司 | A pharmaceutical composition containing indobufen and uses thereof |
-
2018
- 2018-12-05 CN CN201811481531.1A patent/CN109651229A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL172906B1 (en) * | 1993-09-07 | 1997-12-31 | Inst Farmaceutyczny | Method of obtaining indobufene in pharmaceutically advantageous crystalline form |
| CN101270072A (en) * | 2008-02-25 | 2008-09-24 | 北京阜康仁生物制药科技有限公司 | Right-handed indobufen and use for preparing medicament |
| CN101914055A (en) * | 2010-08-02 | 2010-12-15 | 新疆生产建设兵团农六师芳草湖监狱 | Reductive preparation method of imide |
| CN104744339A (en) * | 2013-12-26 | 2015-07-01 | 张云 | Production method of indobufen |
| CN105853364A (en) * | 2016-04-29 | 2016-08-17 | 济南康和医药科技有限公司 | Indobufen solid preparation and preparing method |
| CN106397298A (en) * | 2016-08-11 | 2017-02-15 | 杭州中美华东制药有限公司 | A pharmaceutical composition containing indobufen and uses thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114634440A (en) * | 2020-12-16 | 2022-06-17 | 杭州中美华东制药有限公司 | Indobufen crystal form X and crystal form D and preparation method thereof |
| CN116082218A (en) * | 2020-12-16 | 2023-05-09 | 杭州中美华东制药有限公司 | Indolibufen crystal form D and preparation method thereof |
| CN114634440B (en) * | 2020-12-16 | 2023-05-09 | 杭州中美华东制药有限公司 | Indolibuprofen crystal form X and crystal form D and preparation method thereof |
| CN116082218B (en) * | 2020-12-16 | 2023-08-18 | 杭州中美华东制药有限公司 | Indolibufen crystal form D and preparation method thereof |
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