CN1161971A - Azimycin crystal and preparation method thereof - Google Patents
Azimycin crystal and preparation method thereof Download PDFInfo
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- CN1161971A CN1161971A CN 97101204 CN97101204A CN1161971A CN 1161971 A CN1161971 A CN 1161971A CN 97101204 CN97101204 CN 97101204 CN 97101204 A CN97101204 A CN 97101204A CN 1161971 A CN1161971 A CN 1161971A
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- azithromycin
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Abstract
An ajimycin crystallization and its preparation method mainly features that water-contained ajimycin is dissolved in the mixture of water soluble organic solvent and water, and crystallizing, after drying, the non-twoaquo crystallized-type Ajimycin is obtained. This invention overcomes the defects of the product produced by the existing technology having unstable quality, difficult production and high cost, and the product has product stability better than the exported product, strong fluidity, easy industrialized production and simple preparation method, easily obtained reagent.
Description
The present invention relates to a kind of azithromycin crystallization and preparation method thereof.
Azithromycin (chemical name is N-methyl-9a-azepine-9-deoxidation-9-dihydro Erythromycin A) is derived from Erythromycin A, be a kind of Broad spectrum antibiotics, azithromycin is compared with erythromycin, has has a broad antifungal spectrum, good acid acceptance is arranged, be beneficial to advantages such as oral, pharmacokinetic properties ideal, U.S. Pat .4,512,982, US.4,518,590, US.4,328,334 and US.4,474,768, US.4517359 has disclosed the synthetic method of azithromycin synthetic method and azithromycin hydrate, is about to add water to the apparent slightly muddiness of solution gradually after the first crude product is dissolved in hot ethanol, spend the night and leave standstill from solution crystallization and go out azithromycin and use the same method again and carry out recrystallization, this method weak point is: the azithromycin hydrate of making thus is easily moisture absorption in air, is difficult in the normal temperature preserving, and production has brought very big difficulty to preparation; The non-hygroscopic two water crystallization type azithromycins that European patent EP 298650 is introduced mainly are by tetrahydrofuran (THF), C5-C7 aliphatic hydrocarbon and water mix the back and as solvent azithromycin are carried out crystallization, this method weak point is that tetrahydrofuran (THF) and C5-C7 aliphatic hydrocarbon reagent that this method is used cost an arm and a leg, tetrahydrofuran (THF) and C5-C7 aliphatic hydrocarbon boiling point differ less, difficult solvent recovery.
The objective of the invention is to for solving the easy moisture absorption of azithromycin hydrate, reduction azithromycin Heshui thing crystallization cost makes the azithromycin crystallization have better flowability and pharmaceutical preparation has higher bioavailability and a kind of azithromycin crystallization and preparation method thereof is provided.
One of purpose of the present invention provides a kind of azithromycin crystallization, and it has good flowability and noncrystalline water-content, and specifically the azithromycin crystallization contains planar water less than 4% among the present invention, has following feature:
1, infrared absorption spectrum (KBr) shows following characteristic group frequency
Wave number cm
-1Group
1000-1200 C-O-C
1340-1460 -CH2
1719 -C＝O
1380 N-CH3
2780-3020 -CH3
3400-3600 -OH，H2O
At 3600-3400cm
-1, 3020-2780cm
-1, 1719cm
-1, 1460-1340cm
-1, 1380cm
-1, 1200-1000cm
-1There is charateristic avsorption band at the place.
2, ultra-violet absorption spectrum:
Azithromycin crystallization maximum absorption wavelength λ max=207.7nm among the present invention.
3, ultimate analysis:
Theoretical value (%) C60.93 H9.69 N3.74
Measured value (%) C59.49 H9.87 N3.74
4, heating differential analysis
DSC curve by sample and import reference substance is made comparisons, both curve basically identicals, but the melting heat of sample is littler one times than import reference substance, and 5.83 card/t (sample) and 13.14 card/grams (import reference substance) illustrate that azithromycin of the present invention (sample) contains planar water.
5, nuclear magnetic resonance spectrum (NMR)
A, proton nmr spectra have following feature: ' H-NMR (CDCl2) δ: 2.28[3 '-N (CH3) 2], 2.34 (9a-NCH3),
B, carbon-13 nmr spectra have following principal character:
13C-NMR (CDC13) δ: 178.91 (C-1), 78.14 and 83.32 (C-3, C-5), 36.14 (9a-NCH3), 40.34[3 '-NC (CH3) 2]
6, thermogravimetric analysis (TGA)
Raise with temperature, example weight is 50-105 ℃ of even weightlessness that is nearly flat line.
7, θ ° of interplanar distance I/I0 of χ-ray diffraction: θ ° of interplanar distance I/I0
d(A) d(A)7.58 11.65 7 19.04 4.66 157.80 11.33 26 19.62 4.52 129.40 9.40 20 20.40 4.35 269.80 9.02 100 20.96 4.24 1410.06 8.79 5 21.76 4.08 1011.20 7.89 29 22.60 3.93 911.42 7.74 9 23.46 3.79 711.94 7.41 7 24.52 3.63 812.40 7.09 23 24.76 3.60 913.94 6.35 11 25.22 3.53 715.72 5.63 15 29.50 3.03 516.08 5.51 9 31.24 2.86 516.58 5.34 8 32.76 2.73 418.42 4.81 9 34.86 2.57 418.86 4.70 19 35.14 2.55 4
Two of purpose of the present invention is to provide preparation this azithromycin crystalline method, and it mainly carries out in the mixture with molten solid carbon dioxide solubleness organic solvent of moisture azithromycin and water, and the crystallization after drying obtains.
Detailed step among this preparation method and worker's processing condition are:
Wherein moisture azithromycin: water: the relative weight ratio of water-miscible organic solvent is 1: 30-1000: 9-16.
Water-miscible organic solvent can be ethanol, acetone, Virahol, propyl alcohol, 1.2-propylene glycol, 1.3-propylene glycol, propionitrile, ethylene chlorhydrin, N, N, N ', N '-tetramethyl-urea, N-Methyl pyrrolidone, a kind of in the mixture of vinyl carbinol or above-mentioned substance.
The preferred acetone of organic solvent, ethanol or their mixture.
Dry is vacuum-drying, and the time is 4-5 hour.
Below in conjunction with embodiment the present invention is further described:
Azithromycin crystalline stability experiment the results are shown in following table among the present invention: (temperature 10-32 ℃, humidity 25-80%)
Period of storage (moon) moisture content (%)
0 3.3
1 3.4
3 3.5
6 3.5
12 3.6
17 3.6
By above-mentioned data results as can be seen, azithromycin crystallization of the present invention between 3-4%, in less than 4% scope, can be satisfied industrial production requirement 0,1,3,6,12,17 month sampling and measuring water content.
The crystalline of azithromycin described in the embodiment is prepared:
(1) by U.S. Pat 4517359, the moisture azithromycin 100g that US4474768 prepares, under 50 ℃ of conditions, be dissolved in and dropwise add water to 600ml in the 400ml acetone, slowly stirred 5 hours, rotating speed 200-300 rev/min, be cooled to the room temperature after-filtration, use acetone: mixed solution 3 * 100ml washing of water=1: 2, under 40-50 ℃ of condition vacuum-drying 4-5 hour (0.08MPa-0.09MPa), moisture content gets azithromycin crystallization 86.1g to 3.0-4.0%.
(2) by U.S. Pat 4517359, the moisture azithromycin 100g that US4474768 prepares, under 50 ℃ of conditions, be dissolved in the mixed solution of 400ml ethanol and 400ml acetone and dropwise add water to 600ml, slowly stirred rotating speed 200-300 rev/min 5 hours, and be cooled to room temperature, filter, use acetone: the washings 3 * 100ml of water=1: 1: 4 washs, under 40-50 ℃ of condition vacuum-drying 4-5 hour (0.08MPa-0.09MPa), moisture content gets azithromycin crystallization 86.1g to 3.0-4.0%.
Substantive distinguishing features and technological progress that the present invention is obtained are:
Azithromycin crystallization provided by the present invention is a kind of stable compound, with external import two water Ah Neat mycin crystalline phase ratio has good flowability, is suitable for pharmaceutical preparation, and because institute of the present invention The azithromycin crystallization that provides is non-two water crystallization type azithromycins, therefore in pharmaceutical preparation, has good Bioavilability, this preparation method's agents useful for same is easy to obtain, and is easy to operate.
Claims (7)
1, a kind of azithromycin crystallization is characterized in that containing at ambient temperature and is lower than 4% planar water.
2, azithromycin crystallization according to claim 1, it is characterized in that it has following feature: ultra-violet absorption spectrum maximum absorption wavelength λ max=207.7nm, proton nmr spectra ' H-NMR (CDCl2) δ: 2.28[3 '-N (CH3) 2], 2.34 (9a-NCH3), carbon-13 nmr spectra
13C-NMR (CDCl3) δ: 178.91 (C-1), 78.14 and 83.32 (C-3, C-5), 36.14 (9a-NCH3), 40.34[3 '-NC (CH3) 2], infrared spectra: utilize the Potassium Bromide method to measure this product at 3600-3400cm
-1, 3020-2780cm
-1, 1719cm
-1, 1460-1340cm
-1, 1380cm
-1And 1200-1000cm
-1There is charateristic avsorption band at the place.
3, azithromycin crystalline preparation method according to claim 1 is characterized in that carrying out in the mixture with molten solid carbon dioxide solubleness organic solvent of moisture azithromycin and water that the crystallization after drying obtains.
4, method according to claim 3 is characterized in that wherein moisture azithromycin: water: the relative weight ratio of water-miscible organic solvent is 1: 30-1000: 9-16.
5, according to claim 3 or 4 methods of being advanced, it is characterized in that water-miscible organic solvent can be ethanol, acetone, Virahol, propyl alcohol, 1.2-propylene glycol, 1.3-propylene glycol, propionitrile, ethylene chlorhydrin, N, N, N ', N '-tetramethyl-urea, N-Methyl pyrrolidone, a kind of in the mixture of vinyl carbinol or above-mentioned substance.
6, method according to claim 4 is characterized in that the preferred acetone of organic solvent, ethanol or their mixture.
7, method according to claim 3 is characterized in that the dry vacuum-drying that is, the time is 4-5 hour.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97101204 CN1161971A (en) | 1997-01-03 | 1997-01-03 | Azimycin crystal and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97101204 CN1161971A (en) | 1997-01-03 | 1997-01-03 | Azimycin crystal and preparation method thereof |
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|---|---|
| CN1161971A true CN1161971A (en) | 1997-10-15 |
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| CN 97101204 Pending CN1161971A (en) | 1997-01-03 | 1997-01-03 | Azimycin crystal and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6861413B2 (en) | 2001-05-22 | 2005-03-01 | Pfizer Inc. | Stable non-dihydrate azithromycin oral suspensions |
| US6977243B2 (en) | 2001-05-22 | 2005-12-20 | Pfizer Inc. | Crystal forms of azithromycin |
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| CN100339384C (en) * | 1998-11-30 | 2007-09-26 | 特瓦制药工业有限公司 | Crystalline azithromycin, process for manufacture and pharmaceutical compositions thereof |
| CN101445532B (en) * | 2008-12-30 | 2011-09-21 | 广东东阳光药业有限公司 | Preparation method of azithromycin monohydrate crystal |
| CN105061528A (en) * | 2015-08-05 | 2015-11-18 | 浙江维康药业股份有限公司 | Azithromycin compound and azithromycin soft capsule containing azithromycin compound |
| CN106279312A (en) * | 2016-08-16 | 2017-01-04 | 珠海同源药业有限公司 | A kind of azithromycin compound and combinations thereof thing |
-
1997
- 1997-01-03 CN CN 97101204 patent/CN1161971A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100339384C (en) * | 1998-11-30 | 2007-09-26 | 特瓦制药工业有限公司 | Crystalline azithromycin, process for manufacture and pharmaceutical compositions thereof |
| US7053192B2 (en) | 2001-05-22 | 2006-05-30 | Pfizer Inc. | Crystal forms of azithromycin |
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| US6861413B2 (en) | 2001-05-22 | 2005-03-01 | Pfizer Inc. | Stable non-dihydrate azithromycin oral suspensions |
| US7081525B2 (en) | 2001-05-22 | 2006-07-25 | Pfizer Inc. | Crystal forms of azithromycin |
| US7105179B2 (en) | 2001-05-22 | 2006-09-12 | Pfizer Inc. | Crystal forms of azithromycin |
| US6977243B2 (en) | 2001-05-22 | 2005-12-20 | Pfizer Inc. | Crystal forms of azithromycin |
| US7282486B2 (en) | 2001-05-22 | 2007-10-16 | Pfizer Inc | Crystal forms of azithromycin |
| US7307156B2 (en) | 2001-05-22 | 2007-12-11 | Pfizer Inc. | Crystal forms of azithromycin |
| US7309782B2 (en) | 2001-05-22 | 2007-12-18 | Pfizer Inc. | Crystal forms of azithromycin |
| CN101445532B (en) * | 2008-12-30 | 2011-09-21 | 广东东阳光药业有限公司 | Preparation method of azithromycin monohydrate crystal |
| CN105061528A (en) * | 2015-08-05 | 2015-11-18 | 浙江维康药业股份有限公司 | Azithromycin compound and azithromycin soft capsule containing azithromycin compound |
| CN106279312A (en) * | 2016-08-16 | 2017-01-04 | 珠海同源药业有限公司 | A kind of azithromycin compound and combinations thereof thing |
| CN106279312B (en) * | 2016-08-16 | 2019-08-20 | 珠海同源药业有限公司 | A kind of azithromycin compound and combinations thereof |
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