CN102295576A - Crystal form of tigecycline, and preparation method thereof - Google Patents
Crystal form of tigecycline, and preparation method thereof Download PDFInfo
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- CN102295576A CN102295576A CN201110178594A CN201110178594A CN102295576A CN 102295576 A CN102295576 A CN 102295576A CN 201110178594 A CN201110178594 A CN 201110178594A CN 201110178594 A CN201110178594 A CN 201110178594A CN 102295576 A CN102295576 A CN 102295576A
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Abstract
The invention belongs to the field of medical technology, and relates to a new crystal form of tigecycline, and a preparation method thereof. The A type tigecycline crystal has X-ray powder diffraction peaks positioned on about 5.0, 8.2, 9.2, 10.2, 11.3, 13.0, 13.7, 18.7, 20.5, 21.8, 24.0+-0.2 DEG 2* theta. The B type tigecycline crystal has X-ray powder diffraction peaks positioned on about 5.1, 9.2, 13.0, 13.8, 16.4, 18.7, 20.5, 21.9, 24.2+-0.2 DEG 22* theta.
Description
Technical field:
The invention belongs to medical technical field, relate to new crystal of Tigecycline and preparation method thereof.
Background of invention:
Tigecycline is a kind of tetracycline antibiotics, is the analogue of Minocycline HCl, can be used for antimicrobial agent, and is still effective when concurrent present other antibiotic therapy is failed.As faecalis of methicillin resistant staphylococcus aureus, penicillin-fast streptococcus pneumoniae, vancomycin resistance etc., it still has activity.Tigecycline shows the acute fatal infection that anti-Gram-negative bacteria causes especially.
Tigecycline has the more biological activity of wide region than parent tsiklomitsin and the analogue found up to now thereof, and can be with lower frequency and littler dosed administration.
Tigecycline has been introduced under trade name TYGACIL by Wyeth and the marketization, and TYGACIL sells with the cryodesiccated powder of used for intravenous injection or the form of cake.
Tigecycline is disclosed in United States Patent (USP) 5,494, and in 903 and 5,284,963, its structural formula is as follows:
Tigecycline is the microbiotic with broad spectrum antibiotic activity.Yet Tigecycline is not quite stable.
Usually Tigecycline is to prepare amorphous powder by lyophilize, but owing to Tigecycline is degraded easily, poor stability, these amorphous powders need be prepared, process and store under the hypoxemia cold condition, need special equipment and operation, and cost is very high.
Amorphous compound is made of unordered molecule.And crystalline compounds is the solid form of intramolecularly ordered arrangement, and these arrangements are called lattice, and lattice is made up of structure cell.
The different crystallized form of same compound has different physical propertiess usually, such as fusing point, stability, solvability etc.Generally speaking, the crystallized form of same compound is than the good stability of amorphous substance.
U.S. Patent No. 5,675 has been described in 030 by evaporation from dichloromethane solution and has been obtained Tigecycline crystalline concrete grammar.WO 2006128150 discloses crystal formation and preparation process thereof.But the residual a large amount of methylene dichloride of the Tigecycline that makes thus is difficult for removing, and the poor stability of the product that also obtains than method described in the present invention of stability.
Contrast with five kinds of crystal formations among the Chinese patent CN101248038A and the crystal formation described in the CN101479235, stable crystal form of the present invention is better, and operation is simple relatively.
The method that obtains crystal form X I with methylene dichloride and two kinds of solvents of normal heptane has been described among the WO2009092680.
Described the method for Tigecycline crystal form V I and VIII among the US20100160264, can prepare with the mixed solvent of Nitromethane 99Min. or acetone and acetonitrile, Nitromethane 99Min. toxicity wherein is bigger, and the mixed solvent use is not too convenient.
The preparation of Tigecycline crystal form X is provided among the WO2009062964, has made solvent with the 2-butanols.
More than each crystal form X ray powder diffraction data and crystal formation data contrast table of the present invention as follows: table 1
The invention provides new crystal formation of a kind of Tigecycline and preparation method thereof.Crystal formation provided by the invention has steady quality, and dissolvent residual is few, good water solubility, advantage such as water absorbability is lower, and is clinical easy to use, with low cost.
Summary of the invention:
The present invention discloses the crystallization of a kind of A type Tigecycline, its have be positioned at about 5.0,8.2,9.2,10.2,11.3,13.0,13.7,18.7, the X-ray powder diffraction peak of 20.5,21.8,24.0 ± 0.2 ° of 2 θ.
The present invention also discloses above A type Tigecycline crystalline preparation method, it is characterized in that, comprises that crystallization goes out A type Tigecycline crystalline step from organic solvent.
Wherein said solvent is a Virahol, and its consumption is represented with volume, is that the volume of the weight of 1 times of Tigecycline extremely at room temperature all dissolves the volumes of Tigecycline just.
Preferred A type Tigecycline crystalline preparation method is characterized in that step is as follows: get 1g Tigecycline highly finished product and place flask, add the 40ml Virahol earlier, stirring is warming up to backflow, continue to add Virahol to fully the dissolving, slowly be cooled to separate out crystallization after, be cooled to-10 ℃, continue to stir 2h, filter the crystallization of separating out, and wash with a small amount of cold isopropanol, 40 ℃ of drying under reduced pressure get product.
The present invention also openly contains A type Tigecycline crystalline pharmaceutical composition.
The invention provides another Type B Tigecycline crystallization, its have be positioned at about 5.1,9.2,13.0,13.8,16.4,18.7,20.5,21.9,24.2 ± 0.2 ° of 2 θ X-ray powder diffraction peak.The present invention also provides Type B Tigecycline crystalline preparation method, it is characterized in that, comprises that crystallization goes out Type B Tigecycline crystalline step from organic solvent.Wherein said solvent is an acetone, and its consumption is represented with volume, is that the volume of the weight of 1 times of Tigecycline extremely at room temperature all dissolves the volumes of Tigecycline just.
Preferred Type B Tigecycline crystalline preparation method of the present invention is characterized in that step is as follows: get the 1g Tigecycline and add in the 20ml acetone, stirring at room 4h filters, washing, and 40 ℃ of drying under reduced pressure get product.
The present invention also provides and contains Type B Tigecycline crystalline pharmaceutical composition.
The object of the present invention is to provide a kind of stable crystal formation that contains Tigecycline.Crystal formation steady quality of the present invention, clinical easy to use, cost is low.
The stability data of each crystal formation of the present invention is as follows:
The stability data table of table 2, Tigecycline crystal form A:
| Sequence number | Laying temperature | Purity (%) | Content of isomer (%) |
| 1 | 0 |
99.83 | 0.17 |
| 2 | 25 |
99.80 | 0.20 |
| 3 | 40 |
99.74 | 0.26 |
| 4 | 60 |
99.74 | 0.24 |
The stability data table of table 3, Tigecycline crystal form B:
| Sequence number | The placement condition | Purity (%) | Content of isomer (%) |
| 1 | 0 |
99.88 | 0.12 |
| 2 | 25 |
99.88 | 0.12 |
| 3 | 40 |
99.86 | 0.14 |
| 4 | 60 |
99.13 | 0.25 |
The stable crystal form data sheet of table 4, prior art for preparing:
| Sequence number | The placement condition | Purity (%) | Content of isomer (%) |
| 1 | 0 |
99.47 | 0.41 |
| 2 | 25 |
99.17 | 0.83 |
| 3 | 40 |
99.00 | 1.00 |
| 4 | 60 |
92.14 | 4.45 |
Carry out study on the stability with the crystal formation of the method for the embodiment of the invention 1 and 2 preparation and the crystal formation of prior art for preparing, the result shows that the stability of crystal formation of the present invention is more stable than prior art.
Description of drawings:
Fig. 1, Fig. 2: the x-ray diffractogram of powder of expression Tigecycline crystal form A, and have be positioned at approximately 5.0,8.2,9.2,10.2,11.3,13.0,13.7,18.7, the X-ray powder diffraction peak of 20.5,21.8,24.0 ± 0.2 ° of 2 θ.
Fig. 3, Fig. 4: the x-ray diffractogram of powder of expression Tigecycline crystal form B, and have be positioned at about 5.1,9.2,13.0,13.8,16.4,18.7,20.5,21.9,24.2 ± 0.2 ° of 2 θ X-ray powder diffraction peak.
Embodiment:
Following non-restrictive example is for example understood the method for preparing Tigecycline crystal form A and B.
Embodiment 1
The preparation method of the A crystal formation of Tigecycline is as follows:
Get 1g Tigecycline highly finished product and place flask, add the 40ml Virahol earlier, stirring is warming up to backflow, continue to add Virahol to fully the dissolving, slowly be cooled to separate out crystallization after, be cooled to-10 ℃, continue to stir 2h, filter the crystallization of separating out, and wash with a small amount of cold isopropanol, 40 ℃ of drying under reduced pressure get product.
The preparation method of the B crystal formation of Tigecycline is as follows:
Get the 1g Tigecycline and add in the 20ml acetone, stirring at room 4h filters, washing, and 40 ℃ of drying under reduced pressure get product.
Embodiment 3
Tablet
The A crystal formation of Tigecycline or the B crystal formation and the starch of Tigecycline, Microcrystalline Cellulose mixes, wet granulation, whole grain, compressing tablet promptly gets tablet.
Claims (10)
1.A the crystallization of type Tigecycline, its have be positioned at about 5.0,8.2,9.2,10.2,11.3,13.0,13.7,18.7, the X-ray powder diffraction peak of 20.5,21.8,24.0 ± 0.2 ° of 2 θ.
2. the crystalline preparation method of claim 1 is characterized in that, comprises that crystallization goes out A type Tigecycline crystalline step from organic solvent.
3. the described preparation method of claim 2 is characterized in that, wherein said solvent is a Virahol, and its consumption is represented with volume, is that the volume of the weight of 1 times of Tigecycline extremely at room temperature all dissolves the volumes of Tigecycline just.
4. the described preparation method of claim 2 is characterized in that step is as follows: get the 1g Tigecycline and place flask, add the 40ml Virahol earlier, stirring is warming up to backflow, continue to add Virahol to fully the dissolving, slowly be cooled to separate out crystallization after, be cooled to-10 ℃, continue to stir 2h, filter the crystallization of separating out, and wash with a small amount of cold isopropanol, 40 ℃ of drying under reduced pressure get product.
5. the A type Tigecycline crystalline pharmaceutical composition that contains claim 1.
6.B the crystallization of type Tigecycline, its have be positioned at about 5.1,9.2,13.0,13.8,16.4,18.7,20.5,21.9,24.2 ± 0.2 ° of 2 θ X-ray powder diffraction peak.
7. the crystalline preparation method of claim 6 is characterized in that, comprises that crystallization goes out Type B Tigecycline crystalline step from organic solvent.
8. the described preparation method of claim 7 is characterized in that, wherein said solvent is an acetone, and its consumption is represented with volume, is that the volume of the weight of 1 times of Tigecycline extremely at room temperature all dissolves the volumes of Tigecycline just.
9. the described preparation method of claim 7 is characterized in that step is as follows: get the 1g Tigecycline and add in the 20ml acetone, stirring at room 4h filters, washing, and 40 ℃ of drying under reduced pressure get product.
10. the Type B Tigecycline crystalline pharmaceutical composition that contains claim 6.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008066935A2 (en) * | 2006-11-29 | 2008-06-05 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of tigecycline and processes for preparation thereof |
| CN101248038A (en) * | 2005-05-27 | 2008-08-20 | 惠氏公司 | Crystalline solid forms of tigecycline and methods of preparing same |
| WO2008154058A1 (en) * | 2007-06-12 | 2008-12-18 | Miller James R | Systems and methods for data analysis |
| WO2008155405A1 (en) * | 2007-06-21 | 2008-12-24 | Sandoz Ag | Crystalline solid forms |
| WO2009062964A1 (en) * | 2007-11-14 | 2009-05-22 | Sandoz Ag | Novel solvate |
| CN101479235A (en) * | 2006-04-24 | 2009-07-08 | 特瓦制药工业有限公司 | Tigeycline crystalline forms and processes for preparation thereof |
| WO2009092680A2 (en) * | 2008-01-23 | 2009-07-30 | Sandoz Ag | Antibiotic compounds |
-
2011
- 2011-06-29 CN CN201110178594A patent/CN102295576A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101248038A (en) * | 2005-05-27 | 2008-08-20 | 惠氏公司 | Crystalline solid forms of tigecycline and methods of preparing same |
| CN101479235A (en) * | 2006-04-24 | 2009-07-08 | 特瓦制药工业有限公司 | Tigeycline crystalline forms and processes for preparation thereof |
| WO2008066935A2 (en) * | 2006-11-29 | 2008-06-05 | Teva Pharmaceutical Industries Ltd. | Crystalline forms of tigecycline and processes for preparation thereof |
| WO2008154058A1 (en) * | 2007-06-12 | 2008-12-18 | Miller James R | Systems and methods for data analysis |
| WO2008155405A1 (en) * | 2007-06-21 | 2008-12-24 | Sandoz Ag | Crystalline solid forms |
| WO2009062964A1 (en) * | 2007-11-14 | 2009-05-22 | Sandoz Ag | Novel solvate |
| WO2009092680A2 (en) * | 2008-01-23 | 2009-07-30 | Sandoz Ag | Antibiotic compounds |
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Application publication date: 20111228 |