CN1034734C - Azierythromycin crystal and its preparation method - Google Patents
Azierythromycin crystal and its preparation method Download PDFInfo
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- CN1034734C CN1034734C CN94119821A CN94119821A CN1034734C CN 1034734 C CN1034734 C CN 1034734C CN 94119821 A CN94119821 A CN 94119821A CN 94119821 A CN94119821 A CN 94119821A CN 1034734 C CN1034734 C CN 1034734C
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- water
- azithromycin
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- 239000013078 crystal Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Natural products O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 25
- 229960003276 erythromycin Drugs 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 229960004099 azithromycin Drugs 0.000 claims description 21
- -1 azido erythromycin Chemical compound 0.000 claims description 20
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 20
- 238000002425 crystallisation Methods 0.000 claims description 20
- 230000008025 crystallization Effects 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 8
- 238000002411 thermogravimetry Methods 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000002441 X-ray diffraction Methods 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 2
- 238000002329 infrared spectrum Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- 239000002775 capsule Substances 0.000 description 6
- VQEMDSRIOVZAOM-UHFFFAOYSA-N 4-(4-methylsulfonylphenyl)-1,3-thiazol-2-amine Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=CSC(N)=N1 VQEMDSRIOVZAOM-UHFFFAOYSA-N 0.000 description 5
- 229960004924 azithromycin dihydrate Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 239000013583 drug formulation Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229930006677 Erythromycin A Natural products 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- SRMPHJKQVUDLQE-KUJJYQHYSA-N azithromycin dihydrate Chemical compound O.O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 SRMPHJKQVUDLQE-KUJJYQHYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000001054 red pigment Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new azierythromycin crystal, a preparing method thereof and an application of the new azierythromycin crystal in preparing medicine preparations.
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-9a-azepine-9a-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 0298 afterwards, 650B (1992) is alleged, under the condition that this patent is used, is azithromycin-crystal of hydrate 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 EP0298, 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 shows slight evenly heat absorption between 70～100 ℃; 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 peak sequence number | 2Theta (±0.060 | FWHM | The d-value | Intensity | I/I o |
| 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, dinethylformamide, 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. the preparation of preparation embodiment one crystalline
(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 Dropwise 5 00ml water wherein.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 one 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 (2)
1. new azido erythromycin crystal, it is characterized in that: institute's water content is noncrystalline water, and water content is relatively stable at 4-6% at ambient temperature;
Its thermogravimetric analysis (TGA) is between 30-120 ℃ that to be close to straight line evenly weightless, general weightless about 3.1-3.3% in the time of 100 ℃, and weightlessness 4.2-5.2% during to 140 ℃, the main endotherm(ic)peak of heating differential analysis (DSC) is at 133-135 ℃ or 142-144 ℃; Its infrared spectra is at 3300-3600cm
-1Scope in only at 3429cm
-1Near be single wide absorption peak; Its X-ray diffraction data are: 7.850,9.810,11.190,15.330,19.970,20.460.
2. prepare the method for the azido erythromycin crystal of claim 1 requirement, this method comprises:
A) with azithromycin in 55 ℃ of mixtures that are dissolved in acetone and water, the gained mixture is cooled to room temperature, place in room temperature and separate out crystallization, use acetone then: water is 1: 3 mixed solution washing, and 20 ℃ of vacuum-dryings are to moisture content 4-6%; Or
B) azithromycin is dissolved in acetone in 20 ℃, follows then and stir toward wherein adding entry, slowly be stirred to and separate out crystallization, crystallization acetone: water is that 1: 3 mixed solution washs, and 20 ℃ of vacuum-dryings are to moisture content 4-6%;
A) and b) method in, azithromycin: acetone: the mol ratio of water is 1: 10-150: 30-1500.
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 |
|---|---|---|---|
| CN 93120880 CN1093370A (en) | 1993-12-10 | 1993-12-10 | A kind of new azido erythromycin crystal and preparation method thereof |
| CN93120880.7 | 1993-12-10 | ||
| CN94119821A CN1034734C (en) | 1993-12-10 | 1994-11-25 | Azierythromycin crystal and its preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1114960A CN1114960A (en) | 1996-01-17 |
| CN1034734C true 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) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA03010028A (en) | 2001-05-22 | 2004-02-12 | Pfizer Prod Inc | Crystal forms of azithromycin. |
| US6861413B2 (en) | 2001-05-22 | 2005-03-01 | Pfizer Inc. | Stable non-dihydrate azithromycin oral suspensions |
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| US7468428B2 (en) | 2004-03-17 | 2008-12-23 | App Pharmaceuticals, Llc | Lyophilized azithromycin formulation |
| US7683162B2 (en) | 2004-08-30 | 2010-03-23 | Taro Pharmaceutical Industries Limited | Process of preparing a crystalline azithromycin monohydrate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0298650A2 (en) * | 1987-07-09 | 1989-01-11 | Pfizer Inc. | Azithromycin dihydrate |
-
1994
- 1994-11-25 CN CN94119821A patent/CN1034734C/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0298650A2 (en) * | 1987-07-09 | 1989-01-11 | Pfizer Inc. | Azithromycin dihydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1114960A (en) | 1996-01-17 |
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