CN1523029A - Novel crystal system of Adefovir Dipivoxil and preparation method thereof - Google Patents
Novel crystal system of Adefovir Dipivoxil and preparation method thereof Download PDFInfo
- Publication number
- CN1523029A CN1523029A CNA031509665A CN03150966A CN1523029A CN 1523029 A CN1523029 A CN 1523029A CN A031509665 A CNA031509665 A CN A031509665A CN 03150966 A CN03150966 A CN 03150966A CN 1523029 A CN1523029 A CN 1523029A
- Authority
- CN
- China
- Prior art keywords
- aqueous solution
- adefovir dipivoxil
- adefovir
- solution
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an aldfuwei ester anhydrous crystal product. It is characterized by that XRD: using Cu-K alpha radiation, the X-ray powder diffraction spectrum represented by deg. 2 theta has characteristic absorption peak at about 3.6, 7.8, 15.14, 17.26, 17.98 and 22.24 and DSC: DSC heat-absorbing conversion is implemented at about 94 deg.C. Its preparation method includes the following steps: dissolving aldfuwei ester in aqueous solution of alcohol substance or aqueous solution of ketone-substance or aqueous solution of ether substance which can be dissolved in water or aqueous solution of amide substance which can be dissolved in water or acetonitrile aqueous solution or acetic acid aqueous solution; cooling and crystallizing, and then collecting the invented product from above-mentioned solution. Its yield can be up to above 90%, and its purity can be up to above 99%.
Description
Technical field
The present invention relates to new crystal formation of a kind of nucleoside medicine and preparation method thereof, relate in particular to crystal formation of adefovir dipivoxil novel and preparation method thereof.
Background technology
Adefovir ester (adefovir 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.
Discover that 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 ℃.
Summary of the invention
The technical issues that need to address of the present invention are crystal formations that disclose a kind of adefovir dipivoxil novel and preparation method thereof;
Another technical issues that need to address of the present invention are to disclose a kind of composition that contains the crystal formation of adefovir dipivoxil novel.
The crystal formation of adefovir dipivoxil novel of the present invention is a kind of anhydrous crystal thing, it is characterized in that: 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 3.6,7.8,15.14,17.26,17.98,22.24.
DSC:10 ℃/min scanning, the DSC endothermic transition is at about 94 ℃.
Infrared absorption spectrum: the KBr compressing tablet, at about 3321cm
-1, 3159cm
-1, 1753cm
-1, 1200-1400cm
-1Charateristic avsorption band is arranged.
The invention still further relates to a kind of composition, said composition comprises the described adefovir ester new crystal and the pharmaceutically acceptable carrier for the treatment of significant quantity, preferably contains weight percent content and be 0.1%～99.9% above-mentioned adefovir ester new crystal.
Said carrier comprises vehicle, as water, disintegrating agent, as Magnesium Stearate or talcum powder, tackiness agent, as Xylo-Mucine, sweeting agent, as lactose-hydrate etc.
Adefovir ester new 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.
The preparation method of above-mentioned adefovir dipivoxil anhydrous crystal comprises the steps:
Adefovir ester is dissolved in the aqueous solution of the letones of the aqueous solution of alcohols material of C1～C10 or C3～C10, or the aqueous solution of ether material that can be water-soluble, or the aqueous solution of amide substance that can be water-soluble, or acetonitrile solution, or acetic acid aqueous solution, 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 alcohols, or ketone, ethers, amides, acetonitrile, the acetate equal solvent adds water again, and cooling crystallization is collected adefovir dipivoxil anhydrous crystal of the present invention then from above-mentioned solution.
The adding weight of adefovir ester be the aqueous solution weight 1～60%.
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 weight percent concentration of the organic solvent and the aqueous solution is 10%～50%.
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.
The prepared adefovir dipivoxil anhydrous crystal of the inventive method is higher than 102 ℃ of crystal formation dissolution rates, and 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.
The prepared adefovir dipivoxil anhydrous crystal of the inventive method humidity less than 50% environment under, sealing was preserved more than 1 year, kept stable.
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 ester of the present invention.
Fig. 3 is the DSC figure of adefovir ester 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 drying under reduced pressure gets 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.
Embodiment 2
In the 1500ml aqueous acetone solution, (acetone: water=1: 3), be heated to 60 ℃, dissolving adds the 5g gac, stirs 20 minutes, filters, and filtrate is cooled to 0 ℃, and stirring and crystallizing 5 hours is filtered, and drying under reduced pressure gets product 96g with 100g adefovir ester dissolving crude product.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
In the 1500ml acetonitrile solution, (acetonitrile: water=1: 3), be heated to 70 ℃, dissolving adds the 5g gac, stirs 20 minutes, filters, and filtrate is cooled to 0 ℃, and stirring and crystallizing 5 hours is filtered, and drying under reduced pressure gets product 96g with 100g adefovir ester dissolving crude product.Adopt HPLC to measure, content is 99.4%.Its X-ray powder diffraction spectrogram such as embodiment 1.Infrared absorption pattern such as embodiment 1.
Embodiment 4
In the 1500ml acetic acid aqueous solution, (acetate: water=1: 4), be heated to 40 ℃, dissolving adds the 5g gac, stirs 20 minutes, filters, and filtrate is cooled to 0 ℃, and stirring and crystallizing 5 hours is filtered, and drying under reduced pressure gets product 94g with 100g adefovir ester dissolving crude product.Adopt HPLC to measure, content is 99.6%.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: 2), 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 drying under reduced pressure gets product 94g.Adopt HPLC to measure, content is 99.4%.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, drying under reduced pressure gets product 94g.Adopt HPLC to measure, content is 99.4%.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.
Embodiment 8
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 100.7%.
Comparative Examples 1
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 (11)
1. adefovir dipivoxil anhydrous crystal is characterized in that XRD: use Cu-K α radiation, about 3.6,7.8,15.14,17.26,17.98,22.24 charateristic avsorption band is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent.
2. adefovir dipivoxil anhydrous crystal according to claim 1 is characterized in that, the DSC endothermic transition is at about 94 ℃.
3. adefovir dipivoxil anhydrous crystal according to claim 1 is characterized in that infrared spectra is at about 3321cm
-1, 3159cm
-1, 1753cm
-1, 1200-1400cm
-1Charateristic avsorption band is arranged.
4. composition that contains the claim 1 or 2 for the treatment of significant quantity, 3 described adefovir dipivoxil anhydrous crystals and pharmaceutically acceptable carrier.
5. composition according to claim 4 is characterized in that, described composition is a tablet.
6. according to the preparation method of claim 1 or 2,3 described adefovir dipivoxil anhydrous crystals, it is characterized in that, comprise the steps:
Adefovir ester is dissolved in the aqueous solution of the letones of the aqueous solution of alcohols material of C1～C10 or C3～C10, or the aqueous solution of ether material that can be water-soluble, or the aqueous solution of amide substance that can be water-soluble, or acetonitrile solution, or acetic acid aqueous solution, cooling crystallization is collected adefovir dipivoxil anhydrous crystal of the present invention then from above-mentioned solution;
Or earlier adefovir ester is dissolved in above-mentioned alcohols, or ketone, ethers, amides, acetonitrile, the acetate equal solvent adds water again, and cooling crystallization is collected adefovir dipivoxil anhydrous crystal of the present invention then from above-mentioned solution.
7. method according to claim 6 is characterized in that, the adding weight of adefovir ester is 1～60% of aqueous solution weight.
8. method according to claim 6 is characterized in that, alcohols material is a Virahol, and letones is an acetone, and ether material is a tetrahydrofuran (THF), and amide substance is N, dinethylformamide.
9. method according to claim 6 is characterized in that, the weight percent concentration of the aqueous solution is 10%～50%.
10. method according to claim 6 is characterized in that, is cooled to-30～30 ℃ of crystallizatioies, and the crystallization time is 0.1～10h.
11., it is characterized in that, in the aqueous solution, add the impurity in the proper amount of active carbon adsorbent solution, cooling crystallization again after the filtration according to each described method of claim 5～10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031509665A CN1523029A (en) | 2003-09-12 | 2003-09-12 | Novel crystal system of Adefovir Dipivoxil and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031509665A CN1523029A (en) | 2003-09-12 | 2003-09-12 | Novel crystal system of Adefovir Dipivoxil and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1523029A true CN1523029A (en) | 2004-08-25 |
Family
ID=34286838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031509665A Pending CN1523029A (en) | 2003-09-12 | 2003-09-12 | Novel crystal system of Adefovir Dipivoxil and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1523029A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101190927B (en) * | 2006-11-30 | 2012-04-18 | 天津天士力集团有限公司 | Method for preparing pivaloyloxymethyl 9-[2-(phosphonylmethoxy)ethyl]adenine |
| CN103665044A (en) * | 2013-12-20 | 2014-03-26 | 悦康药业集团有限公司 | Adefovir dipivoxil compound |
-
2003
- 2003-09-12 CN CNA031509665A patent/CN1523029A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101190927B (en) * | 2006-11-30 | 2012-04-18 | 天津天士力集团有限公司 | Method for preparing pivaloyloxymethyl 9-[2-(phosphonylmethoxy)ethyl]adenine |
| CN103665044A (en) * | 2013-12-20 | 2014-03-26 | 悦康药业集团有限公司 | Adefovir dipivoxil compound |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1128805C (en) | Polymorphic clopidogrel hydrogenesulphate form | |
| KR102006200B1 (en) | Crystalline forms of a macrolide, and uses therefor | |
| CN1174991C (en) | Crystal form O of clarithromycin | |
| CN1298322C (en) | Crystalline solids of carvedilol and processes for their preparation | |
| CN1946688A (en) | Atorvastatin calcium in amorphous form | |
| CN1434829A (en) | Processes for preparing clarithromycin polymorphs and novel polymorph IV | |
| CN1384108A (en) | Prepn process of 4''-substituted 9-deoxy-9A aza-9A homoerythromycin derivative | |
| CN100351238C (en) | New derivatives of erythromycin, their preparation process and their use as medicaments | |
| CN1469880A (en) | Pharmaceutical compositions | |
| CN1747934A (en) | Crystalline forms of pitavastatin calcium | |
| CN1537098A (en) | Crystalline forms VI and VII of atorvastatin calcium | |
| CN101054393B (en) | Adefovir dipivoxil anhydrous crystal, preparation method and medicine composition thereof | |
| CN1898211A (en) | Crystal form of quinoline compound and process for its production | |
| CA2506532A1 (en) | Anhydrous crystalline azido cytosine hemisulfate derivative | |
| CN1735620A (en) | Pure levofloxacin hemihydrate and processes for preparation thereof | |
| CN1041933C (en) | Diamine salts of clavulanic acid | |
| CN101360712A (en) | New pleuromutilin derivative and its use | |
| CN111194312A (en) | Novel salts and solid state forms of escitalopram | |
| CN1523029A (en) | Novel crystal system of Adefovir Dipivoxil and preparation method thereof | |
| CN1860120A (en) | Amorphous valganciclovir hydrochloride | |
| JP2005053916A (en) | Method for purifying moxidectin through crystallization | |
| WO2021233434A1 (en) | New crystal form of bictegravir sodium and preparation method therefor | |
| CN103450331A (en) | Method for refining bortezomib | |
| CN1878741A (en) | Novel polymorphs of atovaquone and process of preparation thereof | |
| CN1498890A (en) | Crystalline form of Adefovir ester and preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |