CN107879990A - A kind of new method for preparing III crystal formation Fluconazole bulk drugs - Google Patents
A kind of new method for preparing III crystal formation Fluconazole bulk drugs Download PDFInfo
- Publication number
- CN107879990A CN107879990A CN201610868588.1A CN201610868588A CN107879990A CN 107879990 A CN107879990 A CN 107879990A CN 201610868588 A CN201610868588 A CN 201610868588A CN 107879990 A CN107879990 A CN 107879990A
- Authority
- CN
- China
- Prior art keywords
- crystal formation
- hours
- fluconazole
- preferred
- bulk drugs
- Prior art date
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- 239000013078 crystal Substances 0.000 title claims abstract description 61
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 52
- 239000003814 drug Substances 0.000 title claims abstract description 43
- 229940079593 drug Drugs 0.000 title claims abstract description 40
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960004884 fluconazole Drugs 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000007605 air drying Methods 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 5
- 229940011051 isopropyl acetate Drugs 0.000 claims description 5
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000005755 formation reaction Methods 0.000 abstract description 48
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000000463 material Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 230000000843 anti-fungal effect Effects 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 206010017533 Fungal infection Diseases 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 229940063123 diflucan Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to medicinal chemistry art, there is provided a kind of method for preparing medicinal III crystal formations Fluconazole bulk drug.This preparation method is more easy by the way of recrystallization, obtains the higher III crystal formation Fluconazole bulk drugs of crystal form purity in high yield.
Description
Technical field
The present invention provides a kind of by II crystal formation Fluconazole bulk drug, III crystal formation Fluconazole bulk drug of preparation cheap and easy to get
Method.This method obtains III crystal formation Fluconazole bulk drug, yield phase using II crystal formation Fluconazole bulk drug by converting crystal formation
To higher, the higher III crystal formation Fluconazole bulk drugs of crystal form purity can be obtained.
Background technology
Fluconazole is a kind of medicine for treating fungal infection, is broad-spectrum antifungal medicine, the fungal infection to humans and animals is equal
There is therapeutic action, reported according to domestic and foreign literature, Fluconazole bulk drug has four kinds of crystal formations, respectively I, II, III and hydrate,
There are tablet, capsule, powder-injection and several formulations of parenteral solution in the market, the capsule that the country obtains official written reply is relatively more.Europe
Evaluate report and explicitly point out fluconazole capsule original triturate in continent（Diflucan）For III crystal formation, official written reply is obtained in Chinese market at present
Fluconazole bulk drug be mostly II crystal formation.
Small red delivered according to Guangzhou institute for drug control is tight《The polymorphic and Study on Transformation of Fluconazole》, only original grinds
（Diflucan）1 product is III brilliant, and overseas product is II brilliant and hydrate by remaining 13 domestic product and 4.The world is special
Sharp WO2011/101862A1 elaborates that III Fluconazole bulk drug bioavilability is best and most stable.
Through investigation, it is difficult to obtain that the country, which has III brilliant bulk drug of legal qualification, document Preparation and
Crystal Characterization of a Polymorph, a Monohydrate, and an Ethyl Acetate
Solvate of the Antifungal Fluconazole report the preparation method of III crystal formation, and we pass through experimental verification
It was found that the product crystal form purity obtained with this preparation method is poor, it is the mixture of II crystal formation and III crystal formation, yield is relatively low.For
This, invention is a kind of simple to operate, the higher method for obtaining III higher crystal formation Fluconazole bulk drug of the crystal form purity meaning of yield
Justice is far-reaching.
The content of the invention
It is an object of the invention to the simplicity that the quality requirement according to medicinal compound and commercial scale produce, pass through
The III crystal formation Fluconazole bulk drug available for pharmaceutical use is prepared with the method for recrystallization in organic solvent.It is of the present invention
Method has the characteristics that simple to operate, product purity is high.
The preparation method of III crystal formation Fluconazole bulk drug：The Fluconazole bulk drug of II crystal formation is added in organic solvent I,
Be slowly heated to 40 ~ 60 DEG C of dissolved clarifications, filter while hot, gained filtrate is filtered in -20 ~ 0 DEG C of stirring and crystallizing 4 hours, filter cake in 20 ~
Forced air drying 6 ~ 18 hours at 40 DEG C, obtain III higher crystal formation Fluconazole bulk drug of crystal form purity.Wherein organic solvent I is preferred
Isopropyl acetate；Dissolve by heating preferably 55 ~ 60 DEG C of temperature；Preferably -5 ~ 0 DEG C of recrystallization temperature；Preferably 30 ~ 35 DEG C of drying temperature；It is dry
Preferably 12 hours dry time.
Main advantages of the present invention are：
1st, the present invention is easy to operate, can obtain III higher crystal formation Fluconazole bulk drug of crystal form purity.
2nd, III crystal formations Fluconazole bulk drug property provided by the invention is stable, is advantageous to bulk drug and the storage of finished dosage form medicine
Deposit.(II crystal formation Fluconazole bulk drugs are placed 10 days in the environment that relative humidity is 92.5%, moisture absorption weightening 98%, III crystal formation fluorine health
Azoles bulk drug is placed 10 days in the environment that relative humidity is 92.5%, 6.6%) moisture absorption is increased weight.
3rd, the relevant material for the III crystal formation Fluconazole bulk drug that the present invention obtains is relatively low, and purity is higher.
With reference to specific embodiment, the present invention is expanded on further.These embodiments are merely to illustrate the present invention, and do not have to
In limitation the scope of the present invention.Unless otherwise defined, all specialties and scientific words and the skilled people in this area used in text
Meaning known to member is identical.In addition, any method similar or impartial to described content and material all can be applied to this hair
In bright method.Preferable implementation described in text only presents a demonstration with material to be used.
Brief description of the drawings
Fig. 1 is II crystal formation Fluconazole bulk drug X-RD spectrograms；
Fig. 2 is III crystal formation Fluconazole bulk drug X-RD spectrograms；
Fig. 3 is II crystal formations and III crystal formation mixed crystal bulk drug X-RD spectrograms.
Specific embodiment
Embodiment 1
Repeat document Preparation and Crystal Characterization of a Polymorph, a
Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole side
Method.By II crystal formation Fluconazole bulk drugs（100g）It is placed in isopropanol（1000mL）In, 40 DEG C of stirrings, solution is in suspension.In
Stir 2 hours under 50 ~ 60 DEG C of environment, filter while hot, control the temperature of filtrate stirring and crystallizing 5 days, to be filtered, filter at 20 DEG C or so
Cake is washed with 200ml isopropanols, steamed at 20 DEG C it is empty quick drain to very heavy, about 5 hours, obtain 42.3g White crystalline solids, have
Close material：0.16%, yield 42.30%, X-RD spectrograms show the mixture that products obtained therefrom is II crystal formations and III crystal formations.
Embodiment 2
By II crystal formation Fluconazole bulk drugs（100g）It is placed in methanol（1000mL）In, 50 ~ 60 DEG C of stirrings make its dissolving.In 50 ~
Stir 30 minutes under 60 DEG C of environment, filter while hot, control the temperature of filtrate to be not higher than 0 DEG C, stirring and crystallizing 3 ~ 6 hours, filter, filter
Cake is washed with 200ml methanol, 30 ~ 40 DEG C of forced air dryings 12 hours, obtains 74.60g White crystalline solids, and relevant material is larger：
0.12%, yield 74.60%, X-RD spectrograms show the mixture that products obtained therefrom is II crystal formations and III crystal formations.
Embodiment 3
By II crystal formation Fluconazole bulk drugs（100g）It is placed in methanol（1500mL）In, 40 ~ 50 DEG C of stirrings make its dissolving.In 40 ~
Stir 30 minutes under 50 DEG C of environment, filter while hot, control the temperature of filtrate to be not higher than 0 DEG C, stirring and crystallizing 3 ~ 6 hours, filter, filter
Cake is washed with 200ml methanol, 30 ~ 40 DEG C of forced air dryings 12 hours, obtains 81.10g White crystalline solids, and relevant material is smaller
0.08%, yield 81.10%, X-RD spectrograms show the mixture that products obtained therefrom is II crystal formations and III crystal formations.
Embodiment 4
By II crystal formation Fluconazole bulk drugs（100g）It is placed in isopropanol（1500mL）In, 40 ~ 50 DEG C of stirrings make its dissolving.In 40
Stir 30 minutes under ~ 50 DEG C of environment, filter while hot, control the temperature of filtrate to be not higher than 0 DEG C, stirring and crystallizing 3 ~ 6 hours, filter,
Filter cake is washed with 200ml isopropanols, 30 ~ 40 DEG C of forced air dryings 12 hours, obtains 78.25g White crystalline solid III crystal formation fluorine health
Azoles bulk drug, relevant material is smaller by 0.04%, yield 78.25%, and X-RD spectrograms show that products obtained therefrom is III crystal formations.
Embodiment 5
By II crystal formation Fluconazole bulk drugs（100g）It is placed in isopropyl acetate（1500mL）In, 40 ~ 50 DEG C of stirrings make its dissolving.
Stir 30 minutes under 40 ~ 50 DEG C of environment, filter while hot, control the temperature of filtrate to be not higher than 0 DEG C, stirring and crystallizing 3 ~ 6 hours, take out
Filter, filter cake washs with 200ml isopropanols, 30 ~ 40 DEG C of forced air dryings 12 hours, obtains 81.20g White crystalline solid III crystal formations
Fluconazole bulk drug, relevant material is smaller by 0.039%, yield 81.20%, and X-RD spectrograms show that products obtained therefrom is III crystal formations.
Embodiment 6
By II crystal formation Fluconazole bulk drugs（100g）It is placed in isopropyl acetate（2000mL）In, 40 ~ 50 DEG C of stirrings make its dissolving.
Stir 30 minutes under 40 ~ 50 DEG C of environment, filter while hot, control the temperature of filtrate to be not higher than 0 DEG C, stirring and crystallizing 3 ~ 6 hours, take out
Filter, filter cake washs with 200ml isopropanols, 30 ~ 40 DEG C of forced air dryings 12 hours, obtains 86.50g White crystalline solid III crystal formations
Fluconazole bulk drug, relevant material is smaller by 0.041%, yield 86.50%, and X-RD spectrograms show that products obtained therefrom is II crystal formations and III
The mixture of crystal formation.
Claims (9)
- A kind of 1. new method for preparing III crystal formation Fluconazole bulk drugs, it is characterised in thatII crystal formation Fluconazole bulk drugs are added in organic solvent I, 40~60 DEG C of dissolved clarifications is heated to, filters while hot, gained filter Liquid filtered, filter cake forced air drying 12 hours at 30 ~ 35 DEG C in -5 ~ 0 DEG C of stirring and crystallizing 4 hours.
- 2. according to the method for claim 1, it is characterised in that organic solvent I be methanol, ethanol, isopropanol, ethyl acetate, N-butyl acetate, isopropyl acetate；Wherein, the preferred isopropyl acetate of organic solvent I.
- 3. according to the method for claim 1, it is characterised in that the amount of organic solvent I by throwing II crystal formation bulk drugs 10 ~ 20 times of volumes, wherein it is preferred that 15 times of volumes.
- 4. according to the method for claim 1, it is characterised in that solution temperature is 40 ~ 60 DEG C, wherein preferential 55 ~ 60 DEG C.
- 5. according to the method for claim 1, it is characterised in that recrystallization temperature is -20 ~ 0 DEG C, wherein it is preferred that -5 ~ 0 DEG C.
- 6. according to the method for claim 1, it is characterised in that the crystallization time is 2 ~ 6 hours, wherein it is preferred that 4 hours.
- 7. according to the method for claim 1, it is characterised in that the drying of product uses forced air drying and vacuum drying, wherein It is preferred that forced air drying.
- 8. method according to claim 6, drying temperature is 20 ~ 40 DEG C, wherein it is preferred that 30 ~ 35 DEG C.
- 9. method according to claim 6, drying time selects 6 ~ 18 hours, wherein preferential 12 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610868588.1A CN107879990B (en) | 2016-09-30 | 2016-09-30 | A method of preparing III crystal form Fluconazole bulk pharmaceutical chemicals |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610868588.1A CN107879990B (en) | 2016-09-30 | 2016-09-30 | A method of preparing III crystal form Fluconazole bulk pharmaceutical chemicals |
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| Publication Number | Publication Date |
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| CN107879990A true CN107879990A (en) | 2018-04-06 |
| CN107879990B CN107879990B (en) | 2018-12-07 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383859A (en) * | 2018-04-19 | 2018-08-10 | 西南大学 | Imidazo benzothiazole ether compound and its officinal salt preparation method and application |
-
2016
- 2016-09-30 CN CN201610868588.1A patent/CN107879990B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| KHOULOUD A.ALKHAMIS，ET AL.: "Solid-State Characterization of Fluconazole", 《PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY》 * |
| MAHESWARARAO KARANAM，ET AL.: "New Polymorphs of Fluconazole: Results from Cocrystallization Experiments", 《CRYST.GROWTH DES.》 * |
| MINOR. CAIRA，ET AL.: "Preparation and Crystal Characterizationof a Polymorph, a Monohydrate, and an Ethyl Acetate Solvate of the Antifungal Fluconazole", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
| 林存洁: "氟康唑药物晶型研究", 《万方学位论文数据库》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108383859A (en) * | 2018-04-19 | 2018-08-10 | 西南大学 | Imidazo benzothiazole ether compound and its officinal salt preparation method and application |
| CN108383859B (en) * | 2018-04-19 | 2020-06-26 | 西南大学 | Imidazobenzothiazole ether compound and preparation method and application of pharmaceutically acceptable salt thereof |
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| Publication number | Publication date |
|---|---|
| CN107879990B (en) | 2018-12-07 |
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Address after: No.10 building, Zhengzhou Lingkong biomedical park, northeast corner of the intersection of Huanghai Road and biotechnology 2nd Street, Zhengzhou Airport Economic Comprehensive Experimental Zone, Zhengzhou City, Henan Province Patentee after: Zhengzhou shenlanhai Biomedical Technology Co., Ltd Address before: 100083 Beijing city Haidian District Qinghua East Road No. 16 building 1401 yearhigh Patentee before: BEIJING SHENLANHAI BIOLOGICAL MEDICINE TECHNOLOGY Co.,Ltd. |
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