CN103880904A - Fidaxomicin crystal form I and preparation method thereof - Google Patents
Fidaxomicin crystal form I and preparation method thereof Download PDFInfo
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- CN103880904A CN103880904A CN201410124543.4A CN201410124543A CN103880904A CN 103880904 A CN103880904 A CN 103880904A CN 201410124543 A CN201410124543 A CN 201410124543A CN 103880904 A CN103880904 A CN 103880904A
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- feldamycin
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Abstract
The invention discloses a fidaxomicin crystal form I and a preparation method thereof. An X-ray powder diffraction spectrum of the crystal form has X-ray powder diffraction peaks at 2theta of 4.22 degrees, 7.60 degrees, 8.17 degrees, 9.51 degrees, 10.07 degrees, 11.07 degrees, 11.51 degrees, 12.85 degrees, 13.28 degrees, 15.47 degrees, 16.24 degrees, 18.55 degrees, 19.78 degrees, 20.15 degrees, 20.80 degrees and 21.47 degrees. The crystal form provided by the invention is stable, simple in preparation method, strong in maneuverability, and applicable to industrial production.
Description
Technical field
The present invention relates to a kind of compound crystal formation and crystallization method thereof, more precisely relate to feldamycin crystal formation I and preparation method thereof.
Background technology
Feldamycin (Fidaxomicin) is by the dactylosporangium aurantiacum a kind of novel macrolide antibiotic of 18 ring structures producing that ferments, its structural formula is as shown in formula I, belong to narrow spectral pattern antibacterials, aerobic and the anerobe of main anti-gram-positive, clostridium difficile, also have good anti-microbial effect to methicillin resistant staphylococcus aureus, aerogenesis folder film clostridium and faecalis.The advantages such as feldamycin is mainly used in treating the disease that C. difficile infection causes clinically, and it is low that it has the tendency of resistance of generation, and post antibiotic effect is lasting, cross resistance is low and untoward reaction is few.
Feldamycin is a class multi-crystalline compounds, and common is white needles, flakes crystallization or amorphous powder etc.Same medicine, due to the difference of crystal formation type and purity, makes the physical properties of medicine and stability have significant difference, thereby safety, validity to medicine exert an influence.Although the effect of the C. difficile infection of feldamycin treatment is at present better than vancomycin and metronidazole, but still exist some untoward reactions as nauseating, vomiting, headache, stomachache and diarrhoea etc., therefore, develop safe and effective feldamycin new crystal and just seem very necessary.
At present, both at home and abroad patent, document are fewer to introducing of feldamycin crystal formation preparation method.Patent CN200880009132.3 discloses a kind of preparation method of feldamycin crystal formation: feldamycin be dissolved in to methyl alcohol, acetonitrile, ethyl acetate, chloroform, acetone or contain in the mixed solvent of acetic acid, leave standstill, after filtration, can obtain crystalline deposit.The method solvent for use mostly is the Equations of The Second Kind solvent of international coordination conference (ICH) regulation, can produce very large disadvantageous effect to environment or medicine, and solvent for use amount is larger, thereby causes the waste of solvent, has increased production cost, has limited its industrial applications.
U.S. Pat 2008/0194497A1 obtains 2 θ characteristic peaks in the XRD figure spectrum of feldamycin crystal formation and is positioned at 7.7 °, 15.0 °, 18.8 ° ± 0.2 place.Find after deliberation, this stable crystal form is poor, and after 30 days, carrying out liquid chromatographic detection 40 ℃ of placements has degradation peak to occur, has shortened the shelf-lives of product.
Summary of the invention
One of object of the present invention is to provide a kind of feldamycin crystal formation I of good stability.
Two of object of the present invention is to provide the preparation method of aforementioned feldamycin crystal formation I.
Three of object of the present invention is to provide a kind of medicinal compositions that contains aforementioned feldamycin crystal formation I.
One of object of the present invention is achieved in that
Feldamycin crystal formation I, has X-ray powder diffraction peak at 4.22 °, 7.60 °, 8.17 °, 9.51 °, 10.07 °, 11.07 °, 11.51 °, 12.85 °, 13.28 °, 15.47 °, 16.24 °, 18.55 °, 19.78 °, 20.15 °, 20.80 °, 21.47 ° 2 θ in the X-ray powder diffraction pattern of described crystal formation.
Described feldamycin crystal formation I, X-ray powder diffraction pattern is basic consistent with Fig. 1.
Two of object of the present invention is achieved in that
The preparation method of feldamycin crystal formation I, comprise the following steps: feldamycin is dissolved in solvent, be placed in 0～25 ℃ of crystallization and obtain, described solvent is one or more the mixed solution in ethanol, Virahol, acetone, normal heptane, methylethylketone, or the aqueous solution of one or more mixed solutions.
The preparation method of described feldamycin crystal formation I, comprises the following steps:
1) dissolve: feldamycin is added in described solvent and dissolved, obtain lysate;
2) crystallization, suction filtration: above-mentioned lysate is placed to crystallization, and then suction filtration, obtains filter cake;
3) dry: above-mentioned filter cake vacuum-drying is obtained to feldamycin crystal formation I.
The preparation method of described feldamycin crystal formation I, wherein the dissolving described in step 1) refers to ultrasonic dissolution or heating for dissolving.
The preparation method of described feldamycin crystal formation I, wherein step 2) described in time of placing be 1～7 day, the temperature of placement is 0～25 ℃.
The preparation method of described feldamycin crystal formation I, wherein vacuum-drying described in step 3) refers to 40 ℃, vacuum-drying 1～6 hour.
Three of object of the present invention is achieved in that
Medicinal compositions, described medicinal compositions comprises above-mentioned feldamycin crystal formation I and pharmaceutically acceptable deposited shape agent.
Beneficial effect of the present invention:
1) the feldamycin new crystal that the method for the invention obtains is not reported both at home and abroad.
2) the method for the invention is used toxicity lower solvent, avoided using high toxicity solvent to cause pollution to environment and the injury of human body, and the method solvent load is few, cost is lower, and whole preparation process is more succinct, consuming time shorter, controllability is strong, is applicable to suitability for industrialized production.
3) stable crystal form that prepared by the method for the invention is good, under the condition of high temperature almost without degraded.
Accompanying drawing explanation
The XRD figure spectrum of Fig. 1 feldamycin crystal formation I
TGA and the DSC collection of illustrative plates of Fig. 2 feldamycin crystal formation I
The infrared spectrum contrast of Fig. 3 feldamycin crystal formation I and prior art crystal formation, prior art crystal formation preparation method is with reference to U.S. Pat 20080194497, and in figure, arrow indication 1 is prior art product, and 2 is feldamycin crystal formation I
Embodiment
Following embodiment only realizes method of the present invention for setting forth, and should not be construed as limitation of the present invention.
Feldamycin used in the present invention is from North China Pharmacuetical Group New Drug Research & Development Co., Ltd, and content is 98.2%.The high performance liquid chromatograph (HPLC) that the present invention uses is 996 type detectors, 515 pumps (Waters company).Powder diffractometer model used in the present invention is Bruker D8Advance diffractometer, copper target K radiation(40kV, 40mA), θ-2 θ goniometer, Mo monochromator, Lynxeye detector.Instrument detected with silicon carbide before use.Acquisition software is Diffrac Plus XRDCommander, and analysis software is MDI Jade6.0.Testing conditions is: angular range: 3-40 ° of 2 θ, step-length: 0.02 ° of 2 θ, speed: 0.15s.step
-1.Differential thermal analysis data acquisition is certainly in TA Instruments Q200DSC, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.Thermogravimetric analysis data acquisition is certainly in TA Instruments Q500TGA, and instrument control software is Thermal Advantage, and analysis software is Universal Analysis.
The XRD peak value of the made feldamycin crystal formation of the embodiment of the present invention 1 I:
Table 1
| 2-Theta | d | I% | 2-Theta | d | I% | 2-Theta | d | I% |
| 3.91 | 22.5905 | 44 | 13.90 | 6.3681 | 2.2 | 24.99 | 3.5603 | 7.9 |
| 4.22 | 20.9064 | 41.1 | 15.47 | 5.7214 | 93.3 | 25.70 | 3.4639 | 3.4 |
| 7.60 | 11.6262 | 46.7 | 16.24 | 5.4524 | 7.7 | 26.45 | 3.3672 | 13.5 |
| 8.17 | 10.8125 | 95.8 | 16.72 | 5.2988 | 8.6 | 26.82 | 3.321 | 13.7 |
| 9.51 | 9.2881 | 14.5 | 18.55 | 4.7785 | 100 | 28.32 | 3.1483 | 12.2 |
| 10.07 | 8.7797 | 24.8 | 19.03 | 4.6608 | 17.1 | 28.82 | 3.0954 | 4 |
| 11.07 | 7.9834 | 17.1 | 19.78 | 4.4853 | 51.3 | 29.48 | 3.027 | 6 |
| 11.51 | 7.6833 | 22.2 | 20.15 | 4.4031 | 21 | 32.76 | 2.7315 | 5.7 |
| 11.92 | 7.4205 | 3 | 20.80 | 4.2665 | 6.9 | 33.38 | 2.6822 | 0.4 |
| 12.48 | 7.0897 | 4.6 | 21.47 | 4.1346 | 9.7 | 34.38 | 2.6062 | 2.4 |
| 12.85 | 6.885 | 14.9 | 22.34 | 3.9755 | 14.2 | 37.80 | 2.3782 | 7.4 |
| 13.28 | 6.66 | 8.6 | 23.23 | 3.8258 | 10.9 | ? | ? | ? |
Get 1 gram of feldamycin, with 30 milliliters of normal heptane-methylethylketones (1:1) solution ultrasonic dissolution, dissolve completely rear normal temperature and place 7 days, carry out decompress filter after crystallization, filter cake is placed in 40 ℃ of baking oven vacuum-dryings 1 hour, obtains feldamycin crystal formation I.
The XRD numerical value of made feldamycin crystal formation I is as shown in table 1, as shown in Figure 1, this figure shows collection of illustrative plates: in X-ray powder diffraction pattern, have X-ray powder diffraction peak at 4.22 °, 7.60 °, 8.17 °, 9.51 °, 10.07 °, 11.07 °, 11.51 °, 12.85 °, 13.28 °, 15.47 °, 16.24 °, 18.55 °, 19.78 °, 20.15 °, 20.80 °, 21.47 ° 2 θ.
The TGA of detection feldamycin crystal formation I and DSC collection of illustrative plates are as shown in Figure 2.
Feldamycin crystal formation I prepared by the present invention has X-ray powder diffraction characteristic peak at 4.22 °, 8.17 °, 9.51 °, 11.07 °, 11.51 °, 12.8 °, 13.3 °, 16.24 °, 20.80 ° and 21.47 ° of 2 θ, and in prior art crystal formation, there is no the description of these characteristic peaks and so on.Both infrared datas are at 1736cm as shown in Figure 3
-1, 1696cm
-1, 1161cm
-1, 797cm
-1also there is obvious difference at place.
Get 1 gram of feldamycin, with the aqueous acetone solution ultrasonic dissolution of 40 milliliter 35%, dissolve completely rear 0 ℃ and place 5 days, carry out decompress filter after crystallization, filter cake is placed in 40 ℃ of baking oven vacuum-dryings 4 hours, obtains feldamycin crystal formation I.
Embodiment 3
Get 1 gram of feldamycin, under 50 ℃ of heating, dissolve with 100 milliliters of Virahols, after dissolving completely, be cooled to 10 ℃ of crystallizatioies 24 hours, carry out decompress filter after crystallization, the filtrate after draining is recycled, filter cake is placed in 40 ℃ of baking oven vacuum-dryings 6 hours, obtains feldamycin crystal formation I.
Embodiment 4
Get 1 gram of feldamycin, with the aqueous ethanolic solution of 50 milliliter 50% ultrasonic dissolution at 40 ℃, after dissolving completely, normal temperature is placed 7 days, carries out decompress filter after crystallization, and the filtrate after draining is recycled, filter cake is placed in 40 ℃ of baking oven vacuum-dryings 2 hours, obtains feldamycin crystal formation I.
Embodiment 5
Feldamycin crystal formation I prepared by the present invention and the comparison of prior art product stability, prior art products preparation method is with reference to U.S. Pat 20080194497.Crystal formation I and the prior art product of under 40 ℃ of conditions of high temperature, preserving different time are carried out to HPLC detection, obtain following data:
Table 2
As can be seen from the above data, feldamycin crystal formation I prepared by the present invention has satisfactory stability, almost do not degrade, and prior art product occurs degraded having produced new assorted peak under the condition of high temperature.
Feldamycin crystal formation I of the present invention can make the various pharmaceutical compositions or the formulation that have therepic use and can be used for treating patient according to a conventional method.
Claims (8)
1. feldamycin crystal formation I, it is characterized in that thering is X-ray powder diffraction peak at 4.22 °, 7.60 °, 8.17 °, 9.51 °, 10.07 °, 11.07 °, 11.51 °, 12.85 °, 13.28 °, 15.47 °, 16.24 °, 18.55 °, 19.78 °, 20.15 °, 20.80 °, 21. 47 ° 2 θ in the X-ray powder diffraction pattern of described crystal formation.
2. feldamycin crystal formation I claimed in claim 1, is characterized in that, described X-ray powder diffraction pattern is basic consistent with Fig. 1.
3. the preparation method of the crystal formation of feldamycin described in claim 1 or 2 I, it is characterized in that: feldamycin is dissolved in solvent, being placed in 0～25 ℃ of crystallization obtains, described solvent is one or more the mixed solution in ethanol, Virahol, acetone, normal heptane, methylethylketone, or the aqueous solution of one or more mixed solutions.
4. the preparation method of feldamycin crystal formation I according to claim 3, is characterized in that comprising the following steps:
1) dissolve: feldamycin is added in described solvent and dissolved, obtain lysate;
2) crystallization, suction filtration: above-mentioned lysate is placed to crystallization, and then suction filtration, obtains filter cake;
3) dry: above-mentioned filter cake vacuum-drying is obtained to feldamycin crystal formation I.
5. the preparation method of feldamycin crystal formation I according to claim 4, wherein the dissolving described in step 1) refers to ultrasonic dissolution or heating for dissolving.
6. the preparation method of feldamycin crystal formation I, wherein step 2 according to claim 4) described in time of placing be 1～7 day, the temperature of placement is 0～25 ℃.
7. the preparation method of feldamycin crystal formation I according to claim 3, wherein vacuum-drying described in step 3) refers to 40 ℃, vacuum-drying 1～6 hour.
8. a medicinal compositions, described medicinal compositions comprises feldamycin crystal formation I claimed in claim 1 and pharmaceutically acceptable deposited shape agent.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628820A (en) * | 2014-08-14 | 2015-05-20 | 华北制药集团新药研究开发有限责任公司 | Pristinamycin IA crystal form and preparation method thereof |
| CN114752639A (en) * | 2022-05-30 | 2022-07-15 | 山东胜利生物工程有限公司 | Hainanmycin fermentation medium preparation method and fermentation method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688707A (en) * | 2002-07-29 | 2005-10-26 | 浩鼎生技公司 | Tiacumicin production |
| EP2647643A2 (en) * | 2012-04-05 | 2013-10-09 | OLON S.p.A. | Procedure for the purification of tiacumicin B |
| WO2013170142A1 (en) * | 2012-05-10 | 2013-11-14 | Teva Pharmaceutical Works Ltd. | Solid state forms of fidaxomycin and processes for preparation thereof |
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2014
- 2014-03-28 CN CN201410124543.4A patent/CN103880904B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1688707A (en) * | 2002-07-29 | 2005-10-26 | 浩鼎生技公司 | Tiacumicin production |
| EP2647643A2 (en) * | 2012-04-05 | 2013-10-09 | OLON S.p.A. | Procedure for the purification of tiacumicin B |
| WO2013170142A1 (en) * | 2012-05-10 | 2013-11-14 | Teva Pharmaceutical Works Ltd. | Solid state forms of fidaxomycin and processes for preparation thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104628820A (en) * | 2014-08-14 | 2015-05-20 | 华北制药集团新药研究开发有限责任公司 | Pristinamycin IA crystal form and preparation method thereof |
| CN104628820B (en) * | 2014-08-14 | 2018-06-01 | 华北制药集团新药研究开发有限责任公司 | Pristinamycin I A crystal forms and preparation method thereof |
| CN114752639A (en) * | 2022-05-30 | 2022-07-15 | 山东胜利生物工程有限公司 | Hainanmycin fermentation medium preparation method and fermentation method |
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