CN1114960A - Azierythromycin crystal and its preparation method - Google Patents
Azierythromycin crystal and its preparation method Download PDFInfo
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- CN1114960A CN1114960A CN 94119821 CN94119821A CN1114960A CN 1114960 A CN1114960 A CN 1114960A CN 94119821 CN94119821 CN 94119821 CN 94119821 A CN94119821 A CN 94119821A CN 1114960 A CN1114960 A CN 1114960A
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- water
- azido
- azithromycin
- crystal
- organic solvent
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Abstract
A new azierythromycin crystal, its preparing process, its medicinal preparation and usage are disclosed.
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 ofly to have excellent fluidity and its water content is relatively stable at 4～6% azido erythromycin crystal at ambient temperature, this crystalline preparation method and be used for the purposes of useful in preparing drug formulations.
(chemical name is azithromycin: 9-deoxidation-9 α-azepine-9 α-methyl-9 α-a-homoerythromycin A) derived from Erythromycin A, be a kind of Broad spectrum antibiotics.Azithromycin is compared with erythromycin, have has a broad antifungal spectrum, acidproof, be beneficial to advantages such as oral, pharmacokinetic properties ideal.The chemical structural formula of azithromycin is as follows:
Azithromycin shown in the top structural formula is a known compound.U.S. Pat 4,517,359 (1985) have disclosed a kind of method for preparing azido erythromycin crystal, but do not relate to crystal formation, water content and crystal water.According to European patent EP 0 298 afterwards, 650B (1992) is alleged, under the condition that this patent is used, is the azithromycin hydrate crystallization when azithromycin is separated out in ethanol-water; And, in preparation making processes, " be difficult to operation especially " because it has water absorbability.For this reason, this Patent publish a kind of azithromycin dihydrate more stable and preparation method thereof than azithromycin-hydrate.But according to our experiment and detection, meticulous by the azithromycin dihydrate crystal formation that this method is made, mobile bad, the unfavorable preparation that is directly used in is made; And its crystal water is also unstable, be easy to lose in making the preparation process, so that its preparation is different with raw material, does not show the due feature of dihydrate.In addition, employed tetrahydrofuran (THF) of this method and C
6～C
7Aliphatic hydrocarbon reagent is more expensive, and tetrahydrofuran (THF) and C
6～C
7Boiling point between the aliphatic hydrocarbon reagent differs less, and difficult solvent recovery is very uneconomical.
The objective of the invention is to seek a kind of have better flowability, water content relatively stable, and can be directly used in the new azido erythromycin crystal of preparation and simpler, economic preparation method thereof.
Present inventor's warp is to comprising EP0298,650B has carried out research extensively and profoundly at interior multiple crystallization method, unexpectedly find: under controlled conditions with directly crystallization in the mixture of water-miscible organic solvent and water of azithromycin, can get the metastable azido erythromycin crystal of a kind of new water content fully, prove already that its contained humidity was noncrystalline water.This crystallization has good flowability, can be directly used in the preparation of medicine, as in capsule and the granule, thereby has improved the performance of preparation.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 it has good flowability and metastable noncrystalline water-content.When being directly used in the preparation of pharmaceutical preparation, thermochemical property can not survey and change.
Say that more specifically the new azido erythromycin crystal of the present invention contains 4～6% water, proved that already its contained humidity is noncrystalline water.This crystallization and EP 0298, the azithromycin dihydrate difference that 650B is alleged, it is as follows to have feature:
Infrared absorption: IR (KBr): 3429,2969,2936,2829,1723,1646,1459,1380,1331,1316,1279,1256,1183,1136,1093,1053,1016,996,958,940,900,857,841,795,726,701,646cm
-1
Specific optical rotation:
[α]
20D=-45.0 (C=2, dehydrated alcohol)
Thermogravimetric analysis (TGA):
Be with temperature (20 ℃/minute) example weight that raises that to be close to straight line evenly weightless between 30～120 ℃, generally weightless about 3.1～3.3% in the time of 100 ℃, weightlessness 4.2～5.2% during to 140 ℃.
Heating differential analysis (DSC):
Raise (20 ℃/minute) with temperature, visible broad short projection between 70～100 ℃ shows slight evenly heat absorption; Main endotherm(ic)peak is at 133～135 ℃ or 142～144 ℃.
X-ray diffraction (XRD):
I/I
0＞10 main peaks (three mean value):
| The honeybee sequence number | ???2Thela ??(±0.060 | ?????FWHM | The d-value | Intensity | ???I/I 0 |
| ???3 | ????7.850 | ?????0.165 | ????11.2388 | ????21967 | ????15 |
| ???5 | ????9.810 | ?????0.188 | ????8.9996 | ????132002 | ????100 |
| ???7 | ????11.190 | ?????0.188 | ????7.8936 | ????20574 | ????19 |
| ???15 | ????15.330 | ?????0.212 | ????5.7788 | ????18321 | ????15 |
| ???26 | ????19.970 | ?????0.165 | ????4.4447 | ????14010 | ????10 |
| ???27 | ????20.460 | ?????0.188 | ????4.3372 | ????15642 | ????12 |
The water content 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 azithromycin crystallization in the mixture of water-miscible organic solvent and water.
Say that more specifically method of the present invention is that azithromycin is dissolved in the mixture of hot organic solvent and water, slowly cool off then up to separating out crystallization; Or azithromycin is dissolved in organic solvent, slowly add water then until separating out crystallization.The Tc of the azido erythromycin crystal that the solvent temperature of azithromycin and the present invention are new, generally from room temperature to solvent boiling point, preferred room temperature; Consumption of organic solvent is as the criterion so that azithromycin is all dissolved, and the amount of institute's water is as the criterion so that most of crystallization (more than 85%) is separated out.General azithromycin: organic solvent: water (mol ratio) is 1: 10～150: 30～1500.Filter is at last assembled brilliant, and under controlled conditions room temperature vacuum-drying to water-content 4～6%.
The water-miscible organic solvent of Shi Yonging is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, N in the methods of the invention, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE, 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, comprises that the azido erythromycin crystal that the present invention is new is directly used in the preparation antibiotic formulations, in capsule.
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. the stable experiment of water content under the high humidity:
The azido erythromycin crystal that the present invention is new is placed in relative humidity 75% and 92.5% time room temperature of relative humidity, respectively 0,72, and the variation of moisture content in the detection crystallization in 144 and 240 hours.Under the same terms, use patent EP0298, the azithromycin dihydrate crystallization of 650B method preparation is opposed and is complied same experiment, the results are shown in following table:
The azido erythromycin crystal (A) that the present invention is new
With azithromycin two hydrate crystallizations (B)
The water content stability experiment
| Time (hour | Relative humidity 75% | Relative humidity 92.5% | ||
| The moisture content of A (%) | The moisture content of B (%) | The moisture content of A (%) | The moisture content of B (%) | |
| ???0 ???72 ???144 ???240 | ???4.94 ???5.07 ???5.31 ???5.50 | ????4.60 ????4.70 ????4.85 ????5.05 | ????4.94 ????5.15 ????5.51 ????5.75 | ????4.60 ????4.80 ????4.98 ????5.25 |
Can be seen by last table data: Xin Aqi red pigment of the present invention crystallization is close with the azithromycin dihydrate crystallization on water content stability.Even place for a long time under 92.5% high relative humidity condition, water-content rises few from about 5%, still within 6% limit of regulation, can satisfy the requirement of preparation operation fully.
Two. preparation embodiment-crystalline preparation
(1) preparation of new azido erythromycin crystal of the present invention (method one)
With azithromycin (100g, water-content 3.5%, basically by U.S. Pat 4,517,359 preparation) in 55 ℃ of mixed solutions that are dissolved in 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 then: water is mixed solution 100ml * 3 washings of 1: 3,20 ℃ of vacuum-dryings get title crystallization 90.2g to moisture content 4～6%.This crystalline infrared absorption, specific optical rotation, thermogravimetric analysis, heating differential analysis, X-ray diffraction feature are enumerated in front.
(2) preparation (method two) of the new azido erythromycin crystal of the present invention
(100g, water-content 3.5% is basically by U.S. Pat 4,517,359 preparation) is dissolved in 500ml acetone at 20 ℃ with azithromycin, in 1 hour with stirring toward wherein dripping 500ml water.And then slowly stirred 5 hours, separate out crystallization.Filter is assembled brilliant, uses acetone: water is mixed solution 100ml * 3 washings of 1: 3, and 20 ℃ of vacuum-dryings get title crystallization 92.2g to moisture content 4-6%.This crystalline infrared absorption, specific optical rotation, thermogravimetric analysis, heating differential analysis, X-ray diffraction feature are the same.
Three. the preparation of preparation embodiment-preparation
The azido erythromycin crystal that the present invention is new is because its good fluidity can be directly used in the preparation of capsule easily:
(prescription)
O
#1000 of capsules
Ah agent's erythromycin 250g (pressing the pure calculating of content)
Talcum powder 7.5g
Azithromycin and talcum powder are mixed, cross 30 mesh sieves, be sub-packed in the capsule, make each capsule contain the pure 250mg of azithromycin.
Claims (9)
1. a new azido erythromycin crystal is characterized in that institute's water content is noncrystalline water, and water content is relatively stable at 4-6% at ambient temperature.
2. the azido erythromycin crystal of claim 1, it is characterized in that: have following thermochemistry feature: thermogravimetric analysis (TGA) is intimate straight line between 30-120 ℃ evenly weightless, general weightless about 3.1-3.3% in the time of 100 ℃, weightless 4.2-5.2% during to 140 ℃, the main endotherm(ic)peak of heating differential analysis (DSC) is at 133-135 ℃ or 142-144 ℃.
3. prepare the method for the azido erythromycin crystal of claim 1 requirement, this method comprises: with azithromycin crystallization in water-miscible organic solvent and water.
4. the method for claim 3, wherein the azido erythromycin crystal of claim 1 is that azithromycin crystallization in the mixture of water-miscible organic solvent and water is obtained.
5. the method for claim 3, wherein the azido erythromycin crystal of claim 1 is with azithromycin water-soluble solubleness organic solvent earlier, and then adds elutriation and go out that crystallization obtains.
6. claim 4 or 5 method, wherein azithromycin: water-miscible organic solvent: the mol ratio of water is 1: 10-150: 30-1500.
7. the method for claim 3, wherein water-miscible organic solvent is selected from: methyl alcohol, ethanol, propyl alcohol, Virahol, acetone, N, dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), tetramethylene sulfone, hexamethylphosphoramide, acetonitrile, dioxane, ethylene glycol, dme, pyridine or their mixture.
8. the method for claim 7, wherein water-miscible organic solvent is selected from: ethanol or acetone.
9. the azido erythromycin crystal of claim 1 is used for the method for useful in preparing drug formulations, directly mixes with minor amounts of lubricants, vehicle or carrier comprising the azido erythromycin crystal with claim 1, makes the conventional medicine preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94119821A CN1034734C (en) | 1993-12-10 | 1994-11-25 | Azierythromycin crystal and its preparation method |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93120880.7 | 1993-12-10 | ||
| 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1114960A true CN1114960A (en) | 1996-01-17 |
| CN1034734C CN1034734C (en) | 1997-04-30 |
Family
ID=25743148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94119821A Ceased CN1034734C (en) | 1993-12-10 | 1994-11-25 | Azierythromycin crystal and its preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1034734C (en) |
Cited By (4)
| 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 |
| US7683162B2 (en) | 2004-08-30 | 2010-03-23 | Taro Pharmaceutical Industries Limited | Process of preparing a crystalline azithromycin monohydrate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2066324C1 (en) * | 1987-07-09 | 1996-09-10 | Пфайзер Инк. | Crystalline azithromycin dehydrate, and process for preparation thereof |
-
1994
- 1994-11-25 CN CN94119821A patent/CN1034734C/en not_active Ceased
Cited By (11)
| 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 |
| US7053192B2 (en) | 2001-05-22 | 2006-05-30 | Pfizer Inc. | Crystal forms 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 |
| JP2007161726A (en) * | 2001-05-22 | 2007-06-28 | Pfizer Prod Inc | Crystalline form 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 |
| US7683162B2 (en) | 2004-08-30 | 2010-03-23 | Taro Pharmaceutical Industries Limited | Process of preparing a crystalline azithromycin monohydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1034734C (en) | 1997-04-30 |
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