CN102850289A - Linezolid crystal form VI and preparation method thereof - Google Patents
Linezolid crystal form VI and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a linezolid crystal form VI and a preparation method thereof. In the X-ray powder diffraction spectrum, the crystal form VI powder has absorption peaks at the diffraction angle 2-theta=11.25, 16.27, 16.70, 18.95, 19.69, 22.73, 25.09, 25.31, 26.22, 26.55, 27.54 and 29.60, wherein the error range of the angle 2-theta is +/-0.1. The linezolid crystal form VI provided by the invention has favorable dissolution rate and ideal dissolution effect, and can ensure the medicinal effect; and by using water as the solvent, the preparation method of the crystal form has the advantages of mild technical conditions, no organic solvent to be recycled or discharged, environmental protection and energy saving.
Description
Technical field
The invention belongs to field of medicaments, particularly, relate to a kind of linezolid form VI and preparation method thereof.
Background technology
Linezolid (linezolid), chemistry (S)-N[[3-[3-fluoro-4-(4-morpholinyl) phenyl by name]-2-oxo-5-oxazolidinyl] methyl] ethanamide, the one oxazolidine ketone antimicrobial drug of U.S. Pfizer company research and development, be used for the treatment of the microbemia that vancomycin faecalis (VRE) causes, the microbemia that the pneumonia that methicillin-resistant staphylococcus glucose fungus (MRSA) causes and comprehensive skin infections and penicillin resistance pneumococcus (PRSP) cause.Its structural formula is:
WO 2011/050826 discloses crystal form A and preparation method thereof, the feature angle of diffraction that the powdery diffractometry of this crystal formation possesses (2 θ) peak: 7.6,9.6,13.6,14.9 18.2 18.9,21.2,22.3,25.6,26.9,27.9,29.9; Chinese patent ZL 01803448.9 discloses its II crystal formation and preparation method thereof, feature angle of diffraction (2 θ) peak: 7.10,9.54,13.88,14.23,16.18,16.79,17.69,19.41,19.69,19.93,21.61,22.39,22.84,23.52,24.16,25.28,26.66,27.01,27.77; EP 2100884 discloses the III crystal formation, feature angle of diffraction (2 θ) peak: 7.6,9.6,13.6,14.9,18.2,18.9,21.2,22.3,25.6,26.9,27.9,29.9; CN101262853 discloses the IV crystal formation, feature angle of diffraction (2 θ) peak: 7.4,9.4,13.6,14.8,15.2,15.4,16.3,16.9,18.0,18.8,21.0,22.3,29.7.CN201110132514.9 discloses linezolid form V and preparation method thereof.
The preparation of crystal form A need to consume a large amount of organic solvents, and process regulation is harsh; Crystalline form III, IV need to prepare under hot conditions, and power consumption is large, and destroys product purity easily.And existing linezolid form dissolution rate (result of extraction) is not desirable especially, can not effectively guarantee the medication effect.
Summary of the invention
Technical problem to be solved by this invention provides a kind of linezolid form VI and preparation method thereof, and this crystal formation VI has preferably dissolution rate, and result of extraction is desirable, can guarantee the medication effect; And the preparation method of this crystal formation is take water as solvent, and the preparation process processing condition are gentle, do not have recycling and the discharging of organic solvent, is a kind of environmental protection, energy-conservation preparation method.
The present invention solves the problems of the technologies described above the technical scheme that adopts: the linezolid form VI, it is characterized in that, in its powder X-ray powdery diffractometry spectrum, in diffraction angle 2-theta=11.25,16.27,16.70,18.95,19.69,22.73,25.09,25.31,26.22,26.55,27.54, there is absorption peak at 29.60 places, wherein the limit of error at 2-theta angle is ± 0.2.Because laboratory apparatus error and detection error, the limit of error at 2-theta angle (2 θ angle) is in ± 0.2, all belongs to the scope of the absorption peak of linezolid form VI.
The limit of error at described 2-theta angle is ± 0.05.
The X-ray powder diffraction data of described linezolid form VI are:
Wherein the limit of error of interplanar distance is ± 0.05, and the limit of error of relative intensity is ± 0.2.Given here be relative intensity at the 2-theta angle more than 8 (2 θ angle) locate the scope of absorption peak.Because intensity is too little, it may be the assorted peak that impurity or other conditions are introduced.
In order how to characterize more accurately the feature of azoles amine crystal formation VI, we also define intensity at the 2-theta angle below 8 (2 θ angle) locate the scope of absorption peak, the X-ray powder diffraction data of concrete described linezolid form VI are:
Particularly, the limit of error at described 2-theta angle is ± 0.05.
The preparation method of linezolid form VI comprises the steps: to get the Linezolid raw material and is added to the water, and stirs lower dropping hydrochloric acid and makes its dissolve complete; Then drip aqueous sodium hydroxide solution, the Linezolid solid is separated out, solid is separated out rear filtration, the dry linezolid form VI that gets; Wherein the weight of water is 5～40 times of Linezolid, 0～40 ℃ of solvent temperature, and concentration of hydrochloric acid is 1～12mol/L; The aqueous sodium hydroxide solution mass percent concentration is 10～50%, and recrystallization temperature is 0～40 ℃, crystallization pH=7～12.
Further, the weight of described water is 15 times of Linezolid, and solvent temperature is 0～10 ℃, and concentration of hydrochloric acid is 2mol/L; Described aqueous sodium hydroxide solution concentration is 20%, and recrystallization temperature is 0～10 ℃, crystallization pH=7.
Described Linezolid raw material is purity 98～100% any crystal formations.Any crystal formation here refers to linezolid form I, refers to linezolid form II, refers to linezolid form III, refers to linezolid form IV, refers to linezolid form V, these crystal formations all belong in the prior art disclosed content, can directly buy or obtain by the preparation method that prior art is announced.
The yield of described linezolid form VI is 90-99.9%.
The yield of described linezolid form VI is 95-99.9%
Described aqueous sodium hydroxide solution adopts other alkali-metal oxyhydroxide or carbonate to replace, and perhaps adopts the oxyhydroxide of alkaline-earth metal or carbonate to replace; Hydrochloric acid adopts other aqueous solution of halogen acid, oxalic acid, citric acid, C
1～C
5Lipid acid, C
1～C
7Sulfonic acid is replaced.Other basic metal here refers to count lithium (Li), potassium (K), rubidium (Rb), caesium (Cs), and alkaline-earth metal refers to beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba), six kinds of metallic elements of radium (Ra), C
1～C
5Lipid acid comprises formic acid, acetic acid etc., C
1～C
7Sulfonic acid comprises methylsulfonic acid, ethyl sulfonic acid etc.
With respect to prior art, technique effect of the present invention is: linezolid form VI provided by the invention has preferably dissolution rate, and result of extraction is desirable, can guarantee the medication effect; And the preparation method of this crystal formation is take water as solvent, and the preparation process processing condition are gentle, do not have recycling and the discharging of organic solvent, is a kind of environmental protection, energy-conservation preparation method.
Description of drawings
Fig. 1 is the X-ray powder diffraction pattern of embodiment 1 prepared linezolid form VI.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but embodiments of the present invention are not limited only to following embodiment.
Embodiment 1:
Take by weighing 5g linezolid form A(WO 2011/050826 disclosed crystal form A), join in the 75ml water, be cooled to 0 ℃, add the 2mol/L concentrated hydrochloric acid, it is complete to be stirred to dissolution of solid, temperature (namely keeping solution temperature) is 0 ℃ in keeping, and is 20% potassium hydroxide aqueous solution to wherein dripping mass percent concentration, regulates PH=7, continued insulated and stirred 30 minutes, filter, solid is washed with water to neutrality, and 40 ℃ of drying under reduced pressure get linezolid form VI 4.81g.
The linezolid form VI that present embodiment obtains, its linezolid form VI X-ray powder diffraction pattern such as Fig. 1 (X-coordinate be 2-theta angle (°), ordinate zou is relative intensity (%), the numeral that marks among the figure is interplanar distance ()) shown in, its X-ray powder diffraction data are as shown in the table:
| Relative intensity (%) | The 2-theta angle (°) |
| 1.39 | 8.41804 |
| 13.75 | 11.24812 |
| 0.55 | 13.31043 |
| 8.79 | 16.27104 |
| 20.63 | 16.69993 |
| 1.10 | 17.83709 |
| 9.68 | 18.94828 |
| 100.00 | 19.69455 |
| 4.93 | 20.72817 |
| 10.05 | 22.72681 |
| 4.89 | 23.36915 |
| 2.01 | 24.34820 |
| 22.22 | 25.08582 |
| 30.02 | 25.31276 |
| 59.27 | 26.21630 |
| 8.81 | 26.55392 |
| 7.07 | 26.75020 |
| 18.62 | 27.53844 |
| 3.66 | 28.30218 |
| 15.89 | 29.59834 |
| 7.93 | 31.64664 |
| 2.67 | 32.50975 |
| 4.90 | 33.46500 |
| 4.35 | 33.87351 |
| 1.52 | 34.31385 |
| 2.24 | 35.64286 |
| 1.77 | 36.57159 |
| 4.18 | 37.58091 |
| 1.46 | 38.66345 |
| 4.06 | 39.26159 |
| 1.62 | 39.63966 |
| 1.66 | 40.47451 |
| 4.01 | 41.28160 |
| 2.05 | 42.21925 |
| 4.20 | 43.40900 |
| 1.69 | 45.47648 |
| 0.91 | 46.31878 |
| 2.71 | 47.11649 |
| 1.90 | 48.06066 |
| 2.42 | 48.52858 |
| 0.68 | 49.61245 |
| 1.93 | 50.28118 |
| 1.14 | 50.83246 |
| 1.10 | 51.75365 |
| 2.28 | 52.40887 |
| 1.19 | 53.98171 |
The used linezolid form A of present embodiment is WO 2011/050826 disclosed crystal form A, can be synthetic with existing preparation method, and perhaps buy the commercially available prod and obtain.Present embodiment adopts linezolid form A as raw material.Prepare the linezolid form VI through aforesaid method, the yield of linezolid form VI is 96.7%.
Embodiment 2:
Take by weighing 5g linezolid form II (the disclosed crystal form II of EP1255754), join in the 25ml water, add 3mol/L formic acid, it is complete to be stirred to dissolution of solid, and temperature is 5 ℃ in keeping, to wherein dripping the 32%(mass percent) aqueous sodium hydroxide solution, regulate PH=12, continue to stir 30 minutes, filter, solid is washed with water to neutrality, and 50 ℃ of drying under reduced pressure get linezolid form VI 4.77g.
Embodiment 3:
Take by weighing 5g linezolid form III (the disclosed crystal form II I of EP2100884), join in the 40ml water, add acetic acid, it is complete to be stirred to dissolution of solid, to wherein dripping 50% wet chemical, regulates PH=10 under the room temperature, continue to stir 30 minutes, filter, solid is washed with water to neutrality, and 40 ℃ of drying under reduced pressure get linezolid form VI 4.72g.
Embodiment 4:
Take by weighing 5g linezolid form IV (the disclosed form IV of US20060142283), join in the 75ml water, add Hydrogen bromide, it is complete to be stirred to dissolution of solid, to wherein dripping 10% sodium bicarbonate aqueous solution, regulates PH=7 under the room temperature, continue to stir 30 minutes, filter, solid washes with water, and 50 ℃ of drying under reduced pressure get linezolid form VI 4.74g.
Embodiment 5:
Take by weighing 5g linezolid form V (application number 201110132514.9 disclosed crystal form Vs), join in the 100ml water, stir the lower methylsulfonic acid that adds, be heated to 40 ℃ and make dissolution of solid complete, to wherein dripping 20% aqueous sodium carbonate, regulate PH=10, continue to stir 30 minutes, filter, solid is washed with water to neutrality, and 40 ~ 50 ℃ of drying under reduced pressure get linezolid form VI 4.65g.
In the linezolid form VI powder X-ray powdery diffractometry spectrum of embodiment 2 to embodiment 5 preparation, in diffraction angle 2-theta=11.25,16.27,16.70,18.95,19.69,22.73,25.09,25.31,26.22,26.55,27.54, there is absorption peak at 29.60 places.(powdery diffractometry instrument: AgilentGeminiA Ultra; Analysis condition: bronzing source, collection temperature 193k (error ± 0.2).）
The purity that experiment showed, the Linezolid raw material just can be prepared into satisfactory linezolid form VI 98% when above.In preparation process, if need the higher linezolid form VI of preparation purity, need to select accordingly the higher Linezolid raw material of purity.
Embodiment 6
By the linezolid form VI of embodiment 1 to embodiment 5 preparation, measure its dissolution rate.The measuring method of concrete dissolution rate is: get this product, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2010 C the second method), take 0.1M hydrochloric acid 900ml as solvent, rotating speed is that per minute 50 turns, in accordance with the law operation.In the time of 30 minutes, get solution 10ml, filter, add 0.1M hydrochloric acid and be diluted to the solution that contains approximately Linezolid 10 μ g among every 1ml, as need testing solution; It is an amount of that other gets the Linezolid reference substance, makes the solution that contains approximately Linezolid 10 μ g among every 1ml with 0.1M hydrochloric acid, in contrast product solution.Get above-mentioned two kinds of solution, according to ultraviolet visible spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2010 A), measure respectively absorbancy at the wavelength place of 251nm, press the reference substance relative method and calculate every stripping quantity.The stripping data are as shown in the table.
The stripping data sheet:
Dissolution determination result according to upper table shows that how azoles amine crystal formation VI crystal formation can reach 85.45%, 10 minute at 5 timesharing dissolution rates can reach 98%, for other a few class crystal formations, dissolution rate significantly improves, and result of extraction is ideal, can guarantee the medication effect.And the preparation method of this crystal formation is take water as solvent, and the preparation process processing condition are gentle, do not have recycling and the discharging of organic solvent, is a kind of environmental protection, energy-conservation preparation method.
As mentioned above, can implement preferably the present invention.
Claims (10)
1. linezolid form VI, it is characterized in that, in its powder X-ray powdery diffractometry spectrum, in diffraction angle 2-theta=11.25,16.27,16.70,18.95,19.69,22.73,25.09,25.31,26.22,26.55,27.54, there is absorption peak at 29.60 places, wherein the limit of error at 2-theta angle is ± 0.2.
2. linezolid form VI according to claim 1 is characterized in that, the limit of error at described 2-theta angle is ± 0.05.
3. linezolid form VI according to claim 1 and 2 is characterized in that, the X-ray powder diffraction data of described linezolid form VI are:
Wherein the limit of error of interplanar distance is ± 0.05, and the limit of error of relative intensity is ± 0.2.
4. linezolid form VI according to claim 1 and 2 is characterized in that, the X-ray powder diffraction data of described linezolid form VI are:
5. the preparation method of linezolid form VI is characterized in that, comprises the steps: to get the Linezolid raw material and is added to the water, and stirs lower dropping hydrochloric acid and makes its dissolve complete; Then drip aqueous sodium hydroxide solution, the Linezolid solid is separated out, solid is separated out rear filtration, the dry linezolid form VI that gets; Wherein the weight of water is 5～40 times of Linezolid, 0～40 ℃ of solvent temperature, and concentration of hydrochloric acid is 1～12mol/L; The aqueous sodium hydroxide solution mass percent concentration is 10～50%, and recrystallization temperature is 0～40 ℃, crystallization pH=7～12.
6. the preparation method of described linezolid form VI according to claim 5 is characterized in that the weight of described water is 15 times of Linezolid, and solvent temperature is 0～10 ℃, and concentration of hydrochloric acid is 2mol/L; Described aqueous sodium hydroxide solution concentration is 20%, and recrystallization temperature is 0～10 ℃, crystallization pH=7.
7. according to claim 5 or the preparation method of 6 described linezolid form VI, it is characterized in that described Linezolid raw material is purity 98～100% any crystal formations.
8. according to claim 5 or the preparation method of 6 described linezolid form VI, it is characterized in that the yield of described linezolid form VI is 90-99.9%.
9. according to claim 5 or the preparation method of 6 described linezolid form VI, it is characterized in that the yield of described linezolid form VI is 95-99.9%.
10. according to claim 5 or the preparation method of 6 described linezolid form VI, it is characterized in that described aqueous sodium hydroxide solution adopts other alkali-metal oxyhydroxide or carbonate to replace, perhaps adopt the oxyhydroxide of alkaline-earth metal or carbonate to replace; Hydrochloric acid adopts other aqueous solution of halogen acid, oxalic acid, citric acid, C
1～C
5Lipid acid, C
1～C
7Sulfonic acid is replaced.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503764A (en) * | 2016-01-12 | 2016-04-20 | 江苏豪森药业集团有限公司 | Linezolid crystal form B and preparation method and application thereof |
| CN105524009A (en) * | 2016-01-12 | 2016-04-27 | 江苏豪森药业集团有限公司 | Preparation method of linezolid in type B crystal form |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090062534A1 (en) * | 2007-09-04 | 2009-03-05 | Dipharma Francis S.R.L. | Linezolid crystalline hydrate form and linezolid salts |
| CN102174027A (en) * | 2010-03-11 | 2011-09-07 | 成都自豪药业有限公司 | New crystal form of linezolid and preparation method and application thereof |
| CN102260222A (en) * | 2011-05-20 | 2011-11-30 | 上海医药工业研究院 | Linezolid crystal form V and preparation method thereof |
-
2012
- 2012-09-19 CN CN201210349878.7A patent/CN102850289B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090062534A1 (en) * | 2007-09-04 | 2009-03-05 | Dipharma Francis S.R.L. | Linezolid crystalline hydrate form and linezolid salts |
| CN102174027A (en) * | 2010-03-11 | 2011-09-07 | 成都自豪药业有限公司 | New crystal form of linezolid and preparation method and application thereof |
| CN102260222A (en) * | 2011-05-20 | 2011-11-30 | 上海医药工业研究院 | Linezolid crystal form V and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105503764A (en) * | 2016-01-12 | 2016-04-20 | 江苏豪森药业集团有限公司 | Linezolid crystal form B and preparation method and application thereof |
| CN105524009A (en) * | 2016-01-12 | 2016-04-27 | 江苏豪森药业集团有限公司 | Preparation method of linezolid in type B crystal form |
| CN105503764B (en) * | 2016-01-12 | 2017-09-19 | 江苏豪森药业集团有限公司 | Linezolid form B and its production and use |
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Application publication date: 20130102 Assignee: Chengdu Qingcang Medical Technology Co Ltd Assignor: Chengdu Xinjie Hi-Tech Development Co., Ltd. Contract record no.: 2015510000045 Denomination of invention: Linezolid crystal type VI and preparation method thereof Granted publication date: 20140910 License type: Exclusive License Record date: 20150522 |
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