CN101054393B - Adefovir dipivoxil anhydrous crystal, preparation method and medicine composition thereof - Google Patents
Adefovir dipivoxil anhydrous crystal, preparation method and medicine composition thereof Download PDFInfo
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- CN101054393B CN101054393B CN2006100256028A CN200610025602A CN101054393B CN 101054393 B CN101054393 B CN 101054393B CN 2006100256028 A CN2006100256028 A CN 2006100256028A CN 200610025602 A CN200610025602 A CN 200610025602A CN 101054393 B CN101054393 B CN 101054393B
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- adefovir dipivoxil
- anhydrous crystal
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Abstract
The present invention relates to adefovir dipivoxil anhydrous crystallisate, characterized in that: XRD: radiating with Cu-k alpha , x ray powder diffraction spectrum expressed in 2 theta having characteristic absorption peak at 3.2,6.5,8.6, 15.7,19.6,21.6, DSC: DSC converting due to absorbing heat at 80 degree; infrared absorption spectrum : KBr pellet , characteristic absorption peak being at 3287cm<-1>, 3175cm<-1>, 1753cm<-1>, 1254cm<-1>, 1147 cm<-1>, 1025cm<-1>, 970cm<-1>. The present invention also discloses adefovir dipivoxil anhydrous crystallisate preparation method and its pharmaceutical composition. The inventive adefovir dipivoxil anhydrous crystallisate dissolves quicker than 102 degree crystal form, is high in dissolution, and is stable relative to 94 degree crystal form and not easy to be hygroscopic.
Description
Technical field
The present invention relates to the nucleoside medicine field, relate in particular to adefovir dipivoxil anhydrous crystal, its preparation method and pharmaceutical composition.
Background technology
Adefovir ester (adegovir dipivoxil) is a kind of novel HBV archaeal dna polymerase inhibitor, it is a kind of novel antiviral, its chemical name is: 9-{[2-(two pivaloyl oxygen first) phosphinylidyne methoxy] ethyl } VITAMIN B4, its retroviral infection to humans and animals (as HIV, SIV, FIV etc.), various hepatites virus infections (as HBV, HCV etc.) and dna virus infection (as simplexvirus, HSV1, HSV2 etc.) demonstration place be antiviral activity preferably.Many patents and document have disclosed adefovir ester for information about, as: United States Patent (USP) U.S 4724233; European patent E.P481214; Starrett etc., Antiviral Res. (1992) 19:267～273, and J.Med.Chem. (1994) 37:1857～1864; Benzaria etc., J.Med.Chem. (1996) 39:4958～4965; Zhang Yong etc., Shenyang Pharmaceutical University's journal (2001) 18:95～97.
The crystalline state of the adefovir ester of present disclosed report as the disclosed technology of CN1347695A, is characterized in that: (1) XRD: use Cu-K α radiation, about 6.9 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent; (2) the DSC:DSC endothermic transition is at about 102 ℃.This crystalline state preparation cost is higher, and owing to use the higher solvent of boiling point, dissolvent residual is higher.
Summary of the invention
For solving the problems of the technologies described above, the invention discloses higher, the stable and adefovir dipivoxil anhydrous crystal cheaply of a kind of dissolution rate.
An object of the present invention is to provide a kind of new adefovir dipivoxil anhydrous crystal.
The crystal formation of adefovir dipivoxil novel of the present invention is a kind of anhydrous crystal thing, it shows following characteristic: XRD: use Cu-K α radiation, 40kv/60mA has charateristic avsorption band to spend the X-ray powder diffraction spectrum that 2 θ represent about 3.2,6.5,8.6,15.7,19.6,21.6;
DSC:10 ℃/min scanning, the DSC endothermic transition is at about 80 ℃;
Infrared absorption spectrum: the KBr compressing tablet, at about 3287cm
-1, 3175cm
-1, 1753cm
-1, 1254cm
-1, 1147cm
-1, 1025cm
-1, 970cm
-1Charateristic avsorption band is arranged.
Another object of the present invention provides a kind of pharmaceutical composition that contains adefovir dipivoxil anhydrous crystal, said composition comprises the described adefovir dipivoxil anhydrous crystal for the treatment of significant quantity and pharmaceutically acceptable carrier, preferably contains weight percent content and be 5%～20% above-mentioned adefovir ester new crystal.
Said carrier comprises vehicle, as water; Disintegrating agent is as Magnesium Stearate or talcum powder; Tackiness agent is as Xylo-Mucine; Sweeting agent is as lactose-hydrate etc.
Adefovir dipivoxil anhydrous crystal of the present invention and said composition can be applied to the patient who needs treatment with oral form, and dosage is generally 10mg.
A further object of the present invention provides the preparation method of adefovir dipivoxil anhydrous crystal.
The preparation method of above-mentioned adefovir dipivoxil anhydrous crystal comprises the steps:
Adefovir ester is dissolved in the aqueous solution of organic solvent, and cooling crystallization is collected adefovir dipivoxil anhydrous crystal of the present invention then from above-mentioned solution.
Perhaps earlier adefovir ester is dissolved in above-mentioned organic solvent, adds water again, cooling crystallization is collected adefovir dipivoxil anhydrous crystal of the present invention then from above-mentioned solution.
Described organic solvent is C
1～C
10Alcohols material, or C
3～C
10Letones, or ether material that can be water-soluble, or amide substance that can be water-soluble, or acetonitrile, or acetate.
The preferred Virahol of said alcohols material.
The preferred acetone of said letones.
The preferred tetrahydrofuran (THF) of said ether material.
The preferred N of said amide substance, dinethylformamide.
The adding weight of adefovir ester be the aqueous solution weight 5～30%.
The weight percent concentration of the organic solvent and the aqueous solution is 10%～70%.
Be cooled to-30～30 ℃ of crystallizatioies, the crystallization time is 0.1～10h.
According to the present invention, can in the aqueous solution, add the impurity in the proper amount of active carbon adsorbent solution, cooling crystallization again after the filtration.
Filter, obtain solid, 20-70 ℃ of left and right sides forced air drying is to constant weight.
Adefovir dipivoxil anhydrous crystal of the present invention is higher than 102 ℃ of crystal formation dissolution rates, than 94 ℃ of stable crystal forms, and good fluidity, preparation is convenient, is difficult for moisture absorption, stores easily.
The preparation method is easier, efficient is high, is fit to large-scale industrial production; Cost is low: the used recrystallisation solvent of the present invention is Virahol and water, or acetone and water, and water is main component, cost is lower, this crystallization method yield once can reach more than 90%, the primary crystallization sample purity can reach more than 99%, prepares high purity product easily, has the prospect that heavy industrialization is implemented.
Description of drawings
Fig. 1 is the X-ray powder diffraction spectrogram of adefovir dipivoxil anhydrous crystal of the present invention.
Fig. 2 is the infrared absorption pattern of adefovir dipivoxil anhydrous crystal of the present invention.
Fig. 3 is the DSC figure of adefovir dipivoxil anhydrous crystal of the present invention.
Embodiment
In the 1500ml isopropanol water solution, (Virahol: water=1: 3), be heated to 70 ℃, dissolving adds the 5g gac, filters, and filtrate is cooled to 0 ℃, and stirring and crystallizing 5 hours is filtered, and 50 ℃ of left and right sides forced air dryings get product 95g with 100g adefovir ester dissolving crude product.Adopt HPLC to measure, content is 99.5%.Its X-ray powder diffraction spectrogram is seen Fig. 1, and infrared absorption pattern is seen Fig. 2, and DSC sees Fig. 3.
With 100g adefovir ester dissolving crude product in the 1500ml aqueous acetone solution, (acetone: water=1: 5), be heated to 60 ℃, the dissolving, add the 5g gac, stirred 20 minutes, filter, filtrate is cooled to 0 ℃, stirring and crystallizing 5 hours is filtered, and 30 ℃ of left and right sides forced air dryings get product 91g.Adopt HPLC to measure, content is 99.5%.Its X-ray powder diffraction spectrogram such as embodiment 1, infrared absorption pattern such as embodiment 1.
Embodiment 3
With 100g adefovir ester dissolving crude product in the 1500ml acetonitrile solution, (acetonitrile: water=1: 4), be heated to 70 ℃, the dissolving, add the 5g gac, stirred 20 minutes, filter, filtrate is cooled to 0 ℃, stirring and crystallizing 5 hours is filtered, and 60 ℃ of left and right sides forced air dryings get product 92g.Its X-ray powder diffraction spectrogram such as embodiment 1, infrared absorption pattern such as embodiment 1.
Embodiment 4
With 100g adefovir ester dissolving crude product in the 1500ml acetic acid aqueous solution, (acetate: water=1: 6), be heated to 40 ℃, the dissolving, add the 5g gac, stirred 20 minutes, filter, filtrate is cooled to 0 ℃, stirring and crystallizing 5 hours is filtered, and 70 ℃ of left and right sides forced air dryings get product 90g.Its X-ray powder diffraction spectrogram such as embodiment 1, infrared absorption pattern such as embodiment 1.
Embodiment 5
With 100g adefovir ester dissolving crude product in the 1500ml tetrahydrofuran aqueous solution, (tetrahydrofuran (THF): water=1: 3), be heated to 50 ℃, the dissolving, add the 5g gac, stirred 20 minutes, filter, filtrate is cooled to 0 ℃, stirring and crystallizing 5 hours is filtered, and 50 ℃ of left and right sides forced air dryings get product 94g.Its X-ray powder diffraction spectrogram such as embodiment 1, infrared absorption pattern such as embodiment 1.
Embodiment 6
With 100g adefovir ester dissolving crude product in 1000mlN, the dinethylformamide aqueous solution, (N, dinethylformamide: water=1: 4), be heated to 50 ℃, dissolving adds the 5g gac, stirred 20 minutes, filter, filtrate is cooled to 0 ℃, stirring and crystallizing 5 hours, filter, 60 ℃ of left and right sides forced air dryings get product 90g.Its X-ray powder diffraction spectrogram such as embodiment 1, infrared absorption pattern such as embodiment 1.
Embodiment 7
According to following proportioning, with the product of various carriers and embodiment 1, adopt method preparation well known in the art to become tablet, every contains adefovir ester new crystal 10mg of the present invention.
Composition 10mg tablet dosage
Adefovir ester new crystal 10mg
Lactose-hydrate 85mg
Talcum powder 2.0mg
Magnesium Stearate 1.0mg
Croscarmellose sodium 2.0mg.
The dissolution rate test
Adopt the method for 2000 editions two regulations of Chinese Pharmacopoeia, and adopt 500ml water as dissolution medium, oar method 50rpm carries out the dissolution in vitro test to the preparation of embodiment 7, and 45 minutes average dissolution rate is 100.5%.
Comparative Examples
Adopt the identical method of embodiment 4, the Hepsera tablet that Gilead Sciences company is produced carries out the dissolution in vitro test, and 45 minutes average dissolution rate is 93.3%.
Claims (6)
1. an adefovir dipivoxil anhydrous crystal is characterized in that, its X-ray powder diffraction spectrum is as follows:
The DSC endothermic transition is at about 80 ℃;
Infrared absorption spectrum: the KBr compressing tablet, at about 3287cm
-1, 3175cm
-1, 1753cm
-1, 1254cm
-1, 1147cm
-1, 1025cm
-1, 970cm
-1Charateristic avsorption band is arranged.
2. a composition is characterized in that, comprises described adefovir dipivoxil anhydrous crystal of the claim 1 for the treatment of significant quantity and pharmaceutically acceptable carrier.
3. composition according to claim 2 is characterized in that, the weight percent content of adefovir dipivoxil anhydrous crystal is 5%～20%.
4. composition according to claim 2 is characterized in that described carrier comprises excipient, tackiness agent and sweeting agent.
5. the preparation method of the described adefovir dipivoxil anhydrous crystal of claim 1 is characterized in that, comprises the steps:
A) adefovir ester is dissolved in the aqueous solution of organic solvent, or after adefovir ester is dissolved in organic solvent, adds water,
B) cooling crystallization,
C) collect adefovir dipivoxil anhydrous crystal,
D) with the gained adefovir ester 20-70 ℃ of forced air drying to constant weight;
Described organic solvent is selected from C
1～C
10Alcohol, C
3～C
10Ketone, can be water-soluble ether, can be water-soluble acid amides, acetonitrile or acetate in a kind of.
6. method according to claim 5 is characterized in that, the adding weight of adefovir ester be the aqueous solution weight 5～30%.
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| CN101054393B true CN101054393B (en) | 2011-08-17 |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101343290B (en) * | 2008-05-24 | 2011-02-02 | 广东肇庆星湖生物科技股份有限公司 | Preparation method for adefovir dipivoxil ester waterless crystallization article, prepared adefovir dipivoxil ester waterless crystallization article and uses thereof |
| CN101544670B (en) * | 2009-05-11 | 2011-06-29 | 中国药科大学 | Saccharine adefovir dipivoxil and preparation method thereof |
| CN102827204A (en) * | 2012-09-20 | 2012-12-19 | 中国药科大学 | Eutectic crystal form alpha of saccharin adefovir dipivoxil |
| CN103665044B (en) * | 2013-12-20 | 2015-07-15 | 悦康药业集团有限公司 | Adefovir dipivoxil compound |
| CN104478933A (en) * | 2014-11-13 | 2015-04-01 | 中国药科大学 | Saccharin adefovir dipivoxil eutectic crystal form beta |
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| CN1425673A (en) * | 2003-01-08 | 2003-06-25 | 北京博尔达生物技术开发有限公司 | Adefovir dipivoxil new crystal state, new crystal state composition and its preparing method |
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| CN1425673A (en) * | 2003-01-08 | 2003-06-25 | 北京博尔达生物技术开发有限公司 | Adefovir dipivoxil new crystal state, new crystal state composition and its preparing method |
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Owner name: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY SINO Free format text: FORMER OWNER: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Effective date: 20130427 |
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Effective date of registration: 20130427 Address after: 200137 Shanghai Road, Pudong New Area, No. 378 Patentee after: Shanghai Modern Pharmaceutical Co., Ltd. Patentee after: Shanghai Institute of pharmaceutical industry Patentee after: SINOPHARM RONGSHENG PHARMACEUTICAL CO., LTD. Address before: 200137, Shanghai, Pudong New Area built 387 land Patentee before: Shanghai Modern Pharmaceutical Co., Ltd. Patentee before: Shanghai Institute of pharmaceutical industry |