CN1093370A - A kind of new azido erythromycin crystal and preparation method thereof - Google Patents
A kind of new azido erythromycin crystal and preparation method thereof Download PDFInfo
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- CN1093370A CN1093370A CN 93120880 CN93120880A CN1093370A CN 1093370 A CN1093370 A CN 1093370A CN 93120880 CN93120880 CN 93120880 CN 93120880 A CN93120880 A CN 93120880A CN 1093370 A CN1093370 A CN 1093370A
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- water
- crystallization
- azithromycin
- azido
- organic solvent
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Abstract
The present invention relates to a kind of new azido erythromycin crystal and preparation method thereof.
Description
The present invention relates to a kind of new azido erythromycin crystal, its preparation method and be used for the purposes of useful in preparing drug formulations.Say that more specifically what the present invention relates to is a kind of azithromycin short cylinder crystallization with excellent fluidity and stability, this crystalline preparation method and be used for the purposes of useful in preparing drug formulations.
(chemical name is: 9-deoxidation-9 α-oxa--9 Alpha-Methyl-9 α-a-homoerythromycin A) be derived from Erythromycin A, it is a kind of Broad spectrum antibiotics to azithromycin.Azithromycin is compared with erythromycin, and it has has a broad antifungal spectrum, and is acidproof, is beneficial to advantages such as oral, pharmacokinetic properties ideal.The azithromycin structure is shown in following formula I:
The azithromycin of formula I is a known compound.U.S. Pat .4,474,768 and US patent 4,517,359 disclosed a kind of method for preparing azithromycin-hydrate, but since the water absorbability of azithromycin-hydrate make it very unstable in preparation, thereby in clinical application, be very limited; European patent EP O, 298,650 disclosed a kind of than A Qi red mould-the more stable azithromycin dihydrate of hydrate and preparation method thereof.The azithromycin dihydrate of being prepared by this method is a powdery, can not be directly used in preparation; In addition, employed tetrahydrofuran (THF) of this method and C
6-C
7Aliphatic hydrocarbon reagent is than taking tetrahydrofuran (THF) and C
6-C
7Boiling point between the aliphatic hydrocarbon differs less, difficult solvent recovery, and the water content in the product is wayward.
The objective of the invention is to seek a kind of have better flowability and the new azido erythromycin crystal of stability and simpler, economic preparation method thereof.
The present inventor is through studying extensively and profoundly, unexpectedly find: with the crystallization in the mixture of water-miscible organic solvent and water of azithromycin-hydrate, can get a kind of new short cylinder azido erythromycin crystal, this crystallization has good flowability and stable, can be directly used in the preparation of medicine.The present invention is based on above-mentioned discovery is accomplished.
First purpose of the present invention relates to a kind of new azido erythromycin crystal, and crystallization is the short cylinder crystallization, and it has good flowability and stable, and can be directly used in the preparation of pharmaceutical preparation.
Say that more specifically the new azido erythromycin crystal of the present invention contains the water of 4-6%, it has following X-ray diffraction feature:
2-THETA INT d I/IO
6.180 111.0 14.290 4
7.820 3292 11.296 11
9.800 29070 9.018 100
11.180 5050 7.908 17
12.420 3638 7.121 13
14.580 1936 6.071 7
15.300 3922 5.786 13
15.660 2262 5.654 8
17.060 2197 5.193 8
18.780 1909 4.721 7
19.000 2783 4.667 8
19.540 1909 4.539 7
19.820 2569 4.476 9
20.400 3600 4.350 12
Its diffuse reflectance infrared spectroscopy is as follows:
IR（cm
-1）：3429（OH），2969（-CH
3，-CH
2，-CH-），1728（C＝O），1459（-CH
3，-CH
2，-CH-），1183（C-O-C），1050（C-OH，-C-O-D）。
The stability experiment of the azido erythromycin crystal that the present invention is new will be described in the embodiment of back.
What second purpose of the present invention related to is the method for the new azido erythromycin crystal of preparation the present invention, and it comprises: with the crystallization in the mixture of water-miscible organic solvent and water of azithromycin-hydrating agents.
Say that more specifically method of the present invention is that azithromycin-hydrate is dissolved in the mixture of hot organic solvent and water, slowly cooling or is dissolved in organic solvent with azithromycin-hydrate up to separating out crystallization then, slowly adds water then until separating out crystallization.The Tc of the azido erythromycin crystal that the solvent temperature of azithromycin-hydrate and the present invention are new is not crucial, generally from room temperature to solvent boiling point, preferred room temperature, consumption of organic solvent is as the criterion so that azithromycin-hydrate is all dissolved, the amount of institute's water is as the criterion so that most of knot (more than 78%) is separated out, general azithromycin monohydrate: organic solvent: water (mol ratio)=1: 10-15: 30-1500.Last filtering for crystallizing, and in room temperature vacuum-drying to water-content 4-6%.
The water-miscible organic solvent of Shi Yonging is selected from methyl alcohol, propyl alcohol, N, dinethylformamide, N,N-dimethylacetamide in the methods of the invention, dimethyl sulfoxide (DMSO), tetramethylene sulfone, hexamethylphosphoramide, acetonitrile, dioxane, glycol dimethyl ether, pyridine and their mixture, wherein preferred acetone.
What the 3rd purpose of the present invention related to is the application of the new azido erythromycin crystal of the present invention in the preparation medicament, and it comprises that the azido erythromycin crystal that the present invention is new is directly used in the preparation antibiotic formulations.
The following examples are used to further describe the present invention, but and do not mean that the present invention only limits to this.
One. stability experiment:
The azido erythromycin crystal that the present invention is new (back is represented with A) is placed in relative humidity 20% and 90% time room temperature of relative humidity, respectively 0,12, and the variation of moisture content in the detection crystallization in 24,36,48,60 and 72 hours.Under the same terms, use EPO298, same experiment is done in the azithromycin dihydrate crystallization (back is represented with B) in 650, the results are shown in Table 1:
Table 1
Azido erythromycin crystal of the present invention (A) and EPO298, the stability contrast of 650 azithromycin dihydrate crystallization (B)
Can obviously be seen by data in the top table 1: new azido erythromycin crystal of the present invention obviously is better than EPO298 on stability, the azithromycin dihydrate crystallization in 650.
Two. preparation embodiment
2.1. azithromycin short cylinder crystalline preparation of the present invention
Azithromycin-hydrate (100g with moisture absorption, water-content 2.5%, by U.S. Pat .4,474,768 preparations) under 55 ℃, be dissolved in the mixed solution of 500ml acetone and 500ml water, in 1 hour the gained mixture is cooled to room temperature, separated out crystallization in 5 hours in the room temperature placement, filter is assembled brilliant, uses acetone (1/2) 3 * 100ml washing then, 20 ℃ of vacuum-dryings must be the title crystallization 90.2g of short cylinder to moisture content 4.6 ± 0.2%.
IR（KBr）（cm
-1）：3950，3480，2960，1725，1664，1420，1380，1250，1107，1050，803，671。
[α]
20D=-45.0 ℃ (C=2, dehydrated alcohol)
Ultimate analysis:
Theoretical value (%): C58.14, H9.77, N3.57;
Measured value (%): C58.28, H9.80, N3.56.
2.2. azithromycin short cylinder crystalline preparation of the present invention
Azithromycin-the hydrate of moisture absorption (100g, water-content 2.5%, by U.S. Pat .4,474,768 preparations) is dissolved in 500ml acetone at 20 ℃, in 1 hour with stirring toward wherein dripping 100ml water.And then slowly stirred 5 hours, separate out crystallization, filter is assembled brilliant, and with acetone (1/3) 3 * 100ml washing, 25 ℃ of vacuum-dryings must be the title crystallization 97.2g of short cylinder to moisture content (4.6 ± 0.3%).Infrared and the ultimate analysis data of this crystalline are with in 2.1.
Claims (8)
1, a kind of azido erythromycin crystal is characterized in that, this crystallization is a short cylinder.
2, the method for the azido erythromycin crystal of preparation claim 1 requirement, this method comprises: with the crystallization in water-miscible organic solvent and water of azithromycin-hydrate.
3, the method for claim 2, wherein the A Qi red pigment crystallization of claim 1 is to obtain from the crystallization the mixture of water-miscible organic solvent and water of azithromycin-hydrate.
4, the method for claim 2, wherein the A Qi red pigment crystallization of claim 1 is with azithromycin-water-soluble solubleness organic solvent of hydrate elder generation, and then crystallization obtains in water.
5, claim 3 or 4 method, wherein azithromycin-hydrate: water-soluble organic property solvent: the mol ratio of water is 1: 10-15: 30-1500.
6, the method for claim 2, wherein water-miscible organic solvent is selected from: methyl alcohol, acetone, N, dinethylformamide, N, dinethylformamide, dimethyl sulfoxide (DMSO), tetramethylene sulfone, hexamethylphosphoramide, acetonitrile.Dioxane, ethylene glycol, dme, piperidines or their mixture.
7, the method for claim 6, wherein water-miscible organic solvent is selected from: acetone.
8, the azido erythromycin crystal of claim 1 is used for the method for useful in preparing drug formulations, and it comprises the azido erythromycin crystal of claim 1 directly with pharmaceutical carrier or store the shape agent and is mixed and made into the conventional medicine preparation.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93120880 CN1093370A (en) | 1993-12-10 | 1993-12-10 | A kind of new azido erythromycin crystal and preparation method thereof |
| CN94119821A CN1034734C (en) | 1993-12-10 | 1994-11-25 | Azierythromycin crystal and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 93120880 CN1093370A (en) | 1993-12-10 | 1993-12-10 | A kind of new azido erythromycin crystal and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1093370A true CN1093370A (en) | 1994-10-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 93120880 Pending CN1093370A (en) | 1993-12-10 | 1993-12-10 | A kind of new azido erythromycin crystal and preparation method thereof |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6365574B2 (en) | 1998-11-30 | 2002-04-02 | Teva Pharmaceutical Industries Ltd. | Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereof |
| WO2002094843A1 (en) * | 2001-05-22 | 2002-11-28 | Pfizer Products Inc. | Crystal forms of azithromycin |
| EP1227102B1 (en) * | 2001-01-29 | 2004-03-31 | Alembic Limited | An improved process for the preparation of non-hygroscopic azithromycin dihydrate |
| US6861413B2 (en) | 2001-05-22 | 2005-03-01 | Pfizer Inc. | Stable non-dihydrate azithromycin oral suspensions |
| USRE39087E1 (en) | 1998-08-21 | 2006-05-02 | Apotex, Inc. | Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof |
| EP1652851A1 (en) * | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| CN100354294C (en) * | 2001-05-22 | 2007-12-12 | 辉瑞产品公司 | Crystal forms of azithromycin |
| US7683162B2 (en) | 2004-08-30 | 2010-03-23 | Taro Pharmaceutical Industries Limited | Process of preparing a crystalline azithromycin monohydrate |
| CN104910222A (en) * | 2015-06-29 | 2015-09-16 | 石药集团欧意药业有限公司 | Azithromycin new crystal-form compound and preparation method thereof |
| CN105030704A (en) * | 2015-06-29 | 2015-11-11 | 石药集团欧意药业有限公司 | Azithromycin tablet and preparation method thereof |
| 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 |
-
1993
- 1993-12-10 CN CN 93120880 patent/CN1093370A/en active Pending
Cited By (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| USRE39087E1 (en) | 1998-08-21 | 2006-05-02 | Apotex, Inc. | Azithromycin monohydrate isopropanol clathrate and methods for the manufacture thereof |
| 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 |
| US6365574B2 (en) | 1998-11-30 | 2002-04-02 | Teva Pharmaceutical Industries Ltd. | Ethanolate of azithromycin, process for manufacture, and pharmaceutical compositions thereof |
| EP1227102B1 (en) * | 2001-01-29 | 2004-03-31 | Alembic Limited | An improved process for the preparation of non-hygroscopic azithromycin dihydrate |
| JP2007161726A (en) * | 2001-05-22 | 2007-06-28 | Pfizer Prod Inc | Crystalline form of azithromycin |
| WO2002094843A1 (en) * | 2001-05-22 | 2002-11-28 | Pfizer Products Inc. | Crystal forms of azithromycin |
| EP1652851A1 (en) * | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| US7053192B2 (en) | 2001-05-22 | 2006-05-30 | Pfizer Inc. | Crystal forms of azithromycin |
| EP1671979A1 (en) * | 2001-05-22 | 2006-06-21 | Pfizer Products Inc. | New Cristal Form of Azithromycin |
| 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 |
| EA007618B1 (en) * | 2001-05-22 | 2006-12-29 | Пфайзер Продактс Инк. | Crystalline sesquihydrate azithromycin, pharmaceutical composition and method for treatment based thereon |
| 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 |
| 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 |
| CN100354294C (en) * | 2001-05-22 | 2007-12-12 | 辉瑞产品公司 | Crystal forms of azithromycin |
| US7309782B2 (en) | 2001-05-22 | 2007-12-18 | Pfizer Inc. | Crystal forms of azithromycin |
| US7683162B2 (en) | 2004-08-30 | 2010-03-23 | Taro Pharmaceutical Industries Limited | Process of preparing a crystalline azithromycin monohydrate |
| CN104910222A (en) * | 2015-06-29 | 2015-09-16 | 石药集团欧意药业有限公司 | Azithromycin new crystal-form compound and preparation method thereof |
| CN105030704A (en) * | 2015-06-29 | 2015-11-11 | 石药集团欧意药业有限公司 | Azithromycin tablet and preparation method thereof |
| CN104910222B (en) * | 2015-06-29 | 2018-02-13 | 石药集团欧意药业有限公司 | Azithromycin crystal compound and preparation method thereof |
| CN105030704B (en) * | 2015-06-29 | 2018-09-07 | 石药集团欧意药业有限公司 | Azithromycin and preparation method thereof |
| 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 |
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