CN1524865A - Crystalline forms of adefovir dipivoxil ester - Google Patents
Crystalline forms of adefovir dipivoxil ester Download PDFInfo
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- CN1524865A CN1524865A CNA031098940A CN03109894A CN1524865A CN 1524865 A CN1524865 A CN 1524865A CN A031098940 A CNA031098940 A CN A031098940A CN 03109894 A CN03109894 A CN 03109894A CN 1524865 A CN1524865 A CN 1524865A
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- adefovir ester
- adefovir
- type
- crystal formation
- ester
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- -1 adefovir dipivoxil ester Chemical class 0.000 title claims abstract description 82
- 229960003205 adefovir dipivoxil Drugs 0.000 title abstract description 8
- 229960001997 adefovir Drugs 0.000 claims abstract description 82
- 239000013078 crystal Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 31
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 29
- 230000015572 biosynthetic process Effects 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000000862 absorption spectrum Methods 0.000 claims description 5
- 230000007704 transition Effects 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 229910017488 Cu K Inorganic materials 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 2
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 abstract 1
- 229930024421 Adenine Natural products 0.000 abstract 1
- 229960000643 adenine Drugs 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 239000004278 EU approved seasoning Substances 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 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
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 150000005826 halohydrocarbons Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000011122 softwood Substances 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 235000020985 whole grains Nutrition 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000004049 embossing Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides relates to the crystal system of Adefovir dipivoxi, whose chemical name is 9-[2-[bis(pivalyl oxy) methoxy] pjosphinyl ] methoxy ] ethyl ) adenine, and the invention also relates to a method for preparing adefovir dipivoxil ester crystal system and the composition containing the adefovir dipivoxil ester crystal system.
Description
Invention field
(Adefovir dipivoxil is called for short AD to the present invention relates to adefovir ester.Two (new pentane acyloxy) methoxyl groups of chemical name: 9-[2-[[] phosphinyl] methoxyl group] ethyl) VITAMIN B4) and crystal formation L.In addition, the invention still further relates to method for preparing L type adefovir ester and the composition that contains L type adefovir ester.
Background of invention
Adefovir ester is parent compound 9-[2-(phosphonate group methoxyl group) ethyl] two new pentane acyloxy methyl esters of VITAMIN B4 (" PMEA "), it has antiviral activity to the animal and human.In the bibliographical information in early days, adefovir ester provides with amorphous form.The four kinds of crystal habits and the salt thereof of adefovir ester are disclosed among the Chinese patent CN1347695A.Wherein, crystallization " form 1 " is an anhydrous crystal shape; Crystallization " form 2 " is a hydration shape (dihydrate of AD); Crystallization " form 3 " is a methanol solvate shape; Crystallization " form 4 " is fumarate or the mixture of AD.In addition, in this patent description, other organic acid of AD or the salt or the mixture of mineral acid have been described also.In another piece Chinese patent CN1396170A, the crystallization crystal formation E of another kind of not moisture or other crystallization solvent is disclosed.L type adefovir ester of the present invention is different from any in the crystal formation of being mentioned in the above-mentioned patent, is a kind of crystal habit of new not moisture or other solvent.
In addition, in the preparation AD crystalline method that provides among the patent CN1347695A, expensive, inflammable organic solvent such as n-butyl ether, isopropyl acetate etc. have been used.In the preparation E type AD crystalline method that provides among the patent CN1396170A, crystallization obtains after by solvent evaporated, and this mode is unfavorable for operating in large-scale production process, and since AD for relatively than unstable compounds, thereby in the solvent evaporated process, make product decomposition be difficult to obtain highly purified product in the scale operation easily.Simultaneously, the product that the method for use CN1396170A obtains is difficult to provide the AD with good flow performance or tap density performance, thereby makes AD preparation of compositions or preparation increase difficulty and cost as without operations such as pulverizing, sieve.
Goal of the invention
The L type adefovir ester that the purpose of this invention is to provide a kind of not moisture substantially or other solvent.
Another object of the present invention provides the method for the L type adefovir ester of not moisture substantially or other solvent of preparation.
Another object of the present invention provides the composition that contains L type adefovir ester.
Summary of the invention
The invention provides a kind of L type adefovir ester of non-solventization.In known document, all less than this crystal formation was carried out description.
The feature of L type adefovir ester:
Use Cu-K α radiation, its X-ray powder diffraction spectrum is seen accompanying drawing 1, and there is the peak at its 2 θ angle about 7.5,14.9,16.4,18.6,22.4,26.2, and typically being characterized as about 22.4,26.2 has the peak.The non-solvent crystal formation of in patent CN1347695A, reporting " form 1 ", it is characterized by about 12.7,15.7,20.7 has the peak; The non-solvent crystal formation E crystal formation of reporting in patent CN1396170A, it is characterized by about 15.2,16.4 has the peak.The non-solvent AD crystalline feature of reporting in the X-ray powder diffraction spectrum of L type adefovir ester provided by the invention and the above-mentioned patent is all inequality.
The DSC collection of illustrative plates of L type adefovir ester of the present invention is seen accompanying drawing 2, and its endothermic transition is at about 96 ℃.The crystal formation of in patent CN1347695A, reporting " form 1 ", its endothermic transition is at about 102 ℃; The E crystal formation of reporting in patent CN1396170A, its endothermic transition is at about 94 ℃.
The infrared absorption spectrum that records with the KBr compressing tablet of L type adefovir ester of the present invention is seen accompanying drawing 3, it is characterized by at about 3337,3178,1752,1671,956cm
-1Absorption peak is arranged.
The method for preparing L type adefovir ester has two kinds:
Method one: the oily matter that will contain adefovir ester is dissolved in the optimum solvent, under low temperature, adds in the not optimum solvent, separates out white solid.Filter, behind the drying under reduced pressure, obtain L type adefovir ester.
Method two: with the adefovir ester of other crystal formation, " form 1 " as describing among the CN1347695A is dissolved in the optimum solvent, under low temperature, adds in the not optimum solvent, separates out white solid.Filter, behind the drying under reduced pressure, obtain L type adefovir ester.
In aforesaid method, the optimum solvent of adding is alcohols such as halohydrocarbon such as chloroform, methylene dichloride, methyl alcohol, ethanol, Virahol, and acetone, ethyl acetate, acetonitrile equal solvent, preferred halohydrocarbon, wherein, preferred methylene dichloride.The optimum quantity of solvent (amount of being mentioned all by weight) that adds is preferably 5～10 times for to contain the oily matter of adefovir ester or 1～30 times of other crystal formation adefovir ester.The not optimum solvent that adds is alkanes such as normal hexane, hexanaphthene, sherwood oil, ethers such as ether, isopropyl ether, preferred normal hexane.The not optimum quantity of solvent (amount of being mentioned all by weight) that adds is preferably 50～100 times for to contain the oily matter of adefovir ester or 50～200 times of other crystal formation adefovir ester.The low temperature of crystallization refers to-70～10 ℃ in the aforesaid method, is preferably-50～0 ℃.
The L type adefovir ester that obtains according to the method described above, the purity of being determined by the HPLC method better, can reach more than 99.5% more than 98.5%.
Preparation of the present invention comprises the composition that contains L type adefovir ester and one or more pharmaceutical excipients, optionally, also can contain other therapeutic component.Its vehicle comprises thinner, tackiness agent, disintegrating agent, glidant and lubricant etc.These compositions can be tablet or the capsules that contains 5～150 milligrams of L type adefovir esters.
Tablet can form by randomly suppressing with one or more vehicle.Optionally, can carry out dressing and seal is coated with, embossing or indentation, and can be made into and make the contained activeconstituents slowly-releasing or the tablet of controlled release tablet.
Capsule can by randomly with one or more mixed with excipients, with the direct can of powder; After also can granulating, filled capsules.
Description of drawings
Accompanying drawing 1 is the powder x-ray diffraction figure (XRD figure) of L type adefovir ester of the present invention.
Accompanying drawing 2 is that the difference of L type adefovir ester of the present invention is looked scanning amount heat determination figure (DSC figure).
Accompanying drawing 3 is KBr compressing tablet infrared absorption spectras of L type adefovir ester of the present invention.
Following embodiment only is to describe in detail the present invention, and unrestricted the present invention.
Embodiment
The preparation of embodiment 1 L type adefovir ester
The oily matter that 20 grams is contained adefovir ester is dissolved in 100 milliliters of methylene dichloride, is prepared into the dichloromethane solution that contains adefovir ester.In 2 liters of there-necked flasks, add 1000 ml n-hexanes, stir and be cooled to-10 ℃, in-10 ℃～-5 ℃ dichloromethane solutions that contain adefovir ester that drip aforementioned preparation, separate out a large amount of white solids.Drip to finish ,-10 ℃～-5 ℃ were stirred 10～20 minutes, decompress filter, white solid, 35 ℃ of drying under reduced pressure are to constant weight, L type adefovir ester 12 grams, mp92.5～94.0 ℃, the HPLC method is measured purity: 98.5%.
The preparation of embodiment 2 L type adefovir esters
The oily matter that 20 grams is contained adefovir ester is dissolved in 100 milliliters of anhydrous methanols, is prepared into the methanol solution that contains adefovir ester.In 2 liters of there-necked flasks, add 1000 milliliters of isopropyl ethers, stir and be cooled to-10 ℃, in-10 ℃～-5 ℃ methanol solutions that contain adefovir ester that drip aforementioned preparation, separate out a large amount of white solids.Drip to finish ,-10 ℃～-5 ℃ were stirred 10～20 minutes, decompress filter, white solid, 35 ℃ of drying under reduced pressure are to constant weight, L type adefovir ester 11.5 grams, mp92.5～94.2 ℃, the HPLC method is measured purity: 98.1%.
The preparation of embodiment 3 L type adefovir esters
The oily matter that 20 grams is contained adefovir ester is dissolved in 100 milliliters of methylene dichloride, is prepared into the dichloromethane solution that contains adefovir ester.In 2 liters of there-necked flasks, add 1000 ml n-hexanes, stir and be cooled to-50 ℃, in-50 ℃～-45 ℃ dichloromethane solutions that contain adefovir ester that drip aforementioned preparation, separate out a large amount of white solids.Drip to finish ,-10 ℃～-5 ℃ were stirred 10～20 minutes, decompress filter, white solid, 35 ℃ of drying under reduced pressure are to constant weight, L type adefovir ester 13.5 grams, mp92.6～93.7 ℃, the HPLC method is measured purity: 98.8%.
The preparation of embodiment 4 L type adefovir esters
20 gram " form 1 " adefovir esters that will prepare according to the method that Chinese patent CN 1347695A describes are dissolved in 100 milliliters of methylene dichloride, are mixed with the dichloromethane solution of adefovir ester.In 2 liters of there-necked flasks, add 1000 ml n-hexanes, stir and be cooled to-50 ℃, in-50 ℃～-45 ℃ adefovir ester dichloromethane solutions that drip aforementioned preparation, separate out a large amount of white solids.Drip to finish ,-10 ℃～-5 ℃ were stirred 10～20 minutes, decompress filter, white solid, 35 ℃ of drying under reduced pressure are to constant weight, L type adefovir ester 19 grams, mp92.8～94.2 ℃, the HPLC method is measured purity: 99.5%.
The preparation of embodiment 5 L type adefovir esters
20 gram " form 2 " adefovir esters that will prepare according to the method for Chinese patent CN 1347695A description are dissolved in 100 milliliters of methylene dichloride, behind the adding anhydrous magnesium sulfate drying, filter, and get the adefovir ester dichloromethane solution.In 2 liters of there-necked flasks, add 1000 ml n-hexanes, stir and be cooled to-50 ℃, in-50 ℃～-45 ℃ adefovir ester dichloromethane solutions that drip aforementioned preparation, separate out a large amount of white solids.Drip to finish ,-10 ℃～-5 ℃ were stirred 10～20 minutes, decompress filter, white solid, 35 ℃ of drying under reduced pressure are to constant weight, L type adefovir ester 18 grams, mp92.9～93.9 ℃, the HPLC method is measured purity: 99.2%.
Embodiment 6～embodiment 16
To contain adefovir ester oily matter, according to the working method of embodiment 1～5, investigate the situation of preparation L type adefovir ester under different condition, the results are shown in following table.Wherein, the amount optimum or not optimum solvent of adding is the multiple that contains the oily matter of adefovir ester, all by weight.
| Embodiment | Optimum solvent | Optimum solvent adding amount | Not optimum solvent | Not optimum solvent adding amount | Recrystallization temperature (℃) | Crystal formation |
| ????6 | Acetone | ????10 | Normal hexane | ????100 | ???-50℃～ ???-45℃ | ????L |
| ????7 | Ethanol | ????15 | Normal hexane | ????100 | ???-50℃～ ???-45℃ | ????L |
| ????8 | Virahol | ????20 | Normal hexane | ????200 | ???-50℃～ ???-45℃ | ????L |
| ????9 | Chloroform | ????10 | Normal hexane | ????100 | ???-50℃～ ???-45℃ | ????L |
| ????10 | Ethyl acetate | ????15 | Normal hexane | ????150 | ???-50℃～ ???-45℃ | ????L |
| ????11 | Acetonitrile | ????15 | Normal hexane | ????200 | ???-50℃～ ???-45℃ | ????L |
| ????12 | Methylene dichloride | ????10 | Hexanaphthene | ????100 | ???-50℃～ ???-45℃ | ????L |
| ????13 | Methylene dichloride | ????10 | Sherwood oil | ????150 | ???-50℃～ ???-45℃ | ????L |
| ????14 | Methylene dichloride | ????8 | Ether | ????100 | ???-50℃～ ???-45℃ | ????L |
| ????15 | Methylene dichloride | ????10 | Normal hexane | ????100 | ???-70℃～ ???-55℃ | ????L |
| ????16 | Methylene dichloride | ????10 | Normal hexane | ????100 | ????20℃ | Mixed crystal |
The physical property of embodiment 17 L type adefovir dipivoxil crystals characterizes
Analyze the crystallization of L type adefovir ester by X-ray powder diffraction (XRD).(condition determination: Cu K
α 1Line (λ
α 1=1.54056 ), monochromatic radiation, 50kV 80mA excites; Testing tool: Japanese Rigaku D/MAX RC type powder crystal diffractometer of science.) measurement result shows that L type adefovir dipivoxil crystal has characteristic XRD peak (representing to spend 2 θ) about 7.5,14.9,16.4,18.6,22.4,26.2.The representative XRD figure of L type adefovir ester is seen accompanying drawing 1.
Look the crystallization that L type adefovir ester is analyzed in scanning amount heat determination (DSC) by difference.(condition determination: 30 ℃ of starting temperatures, 150 ℃ of final temperatures, temperature rise rate: 10.0 ℃/min; Testing tool: NETZSCH DSC 204.) measurement result shows that the characteristic endothermic transition of L type adefovir ester is at about 96 ℃.The difference of L type adefovir ester is looked the scanning amount heat determination and be the results are shown in accompanying drawing 2.
Crystallization by infrared absorption (IR) spectroscopic analysis L type adefovir ester.(measuring method: adopt the KBr pressed disc method; Testing tool: Nicolet (Buddhist nun's high-tensile strength) Nexus-470 of company type fourier transform infrared spectrometer.) measurement result shows infrared absorption spectrum (KBr, the cm of L type adefovir dipivoxil crystal
-1) about 3337,3178,2969,1752,1671,1149,956 characteristic spectrum belt is arranged.The infrared absorption spectrum of L type adefovir ester is seen accompanying drawing 3.
Fusing point with traditional fusing point assay L type adefovir ester.(measuring method: sample is put at 70 ℃, and the speed with 1 ℃/min heats up then) measurement result shows that L type adefovir dipivoxil crystal melts between 92.5～94.5 ℃.
Find that by Ka Er-Fei Xiu titration the water content of L type adefovir ester is less than 0.5%.
Embodiment 18 contains the preparation of L type adefovir ester tablet
Prepare every tablet of tablet that contains L type adefovir ester 5mg or 120mg as follows.
| Component | ????5mg ????％?w/w | ????120mg ????％??w/w |
| L type adefovir ester | ????4.0 | ????50.0 |
| Lactose | ????59.0 | ????13.0 |
| Microcrystalline Cellulose | ????20.0 | ????20.0 |
| Pregelatinized Starch | ????5.0 | ????5.0 |
| Croscarmellose sodium | ????5.0 | ????5.0 |
| Talcum powder | ????6.0 | ????6.0 |
| Magnesium Stearate | ????1.0 | ????1.0 |
| Water | In right amount | In right amount |
| Tablet weight (mg) | ????125 | ????240 |
The preparation method who contains the tablet of L type adefovir ester mixes above-mentioned vehicle and L type adefovir ester, and it is an amount of to add entry, the system softwood, the granulation of sieving, wet granular are in 40 ℃ of air seasonings, and whole grain sieves, add Magnesium Stearate and talcum powder and mix, compacting in flakes.
Embodiment 19 contains the capsular preparation of L type adefovir ester
Prepare as follows every contain L type adefovir ester 5mg or 120mg capsule.
| Component | ????5mg ????％??w/w | ????120mg ????％??w/w |
| L type adefovir ester | ????3.8 | ????50.0 |
| Lactose | ????85.2 | ????39.0 |
| Pregelatinized Starch | ????5.0 | ????5.0 |
| Croscarmellose sodium | ????5.0 | ????5.0 |
| Silicon-dioxide | ????1.0 | ????1.0 |
| Water | In right amount | In right amount |
| Loading amount (mg) | ????130 | ????240 |
The manufacture method that contains L type adefovir ester capsule is that above-mentioned vehicle and L type adefovir ester are mixed, and it is an amount of to add entry, the system softwood, and the granulation of sieving, wet granular is in 40 ℃ of air seasonings, and the whole grain that sieves adds silicon-dioxide and mixes the can capsule.
Claims (11)
1. the crystal formation of an adefovir ester is characterized in that the crystallization of described crystalline adefovir ester for not moisture and other solvent, is referred to as crystal formation L.
2. crystal formation as claimed in claim 1 is characterized in that, it uses the alpha-emitting X-ray powder diffraction of Cu-K spectrographic 2 θ angles about 22.4 and 26.2 the peak to be arranged.
3. crystal formation as claimed in claim 1 is characterized in that, its infrared absorption spectrum is at about 3337,3178,1752,1671,956cm
-1There is absorption peak at the place.
4. crystal formation as claimed in claim 1 is characterized in that, its DSC endothermic transition is at about 96 ℃.
5. a method for preparing L crystal formation adefovir ester is characterized in that adefovir ester is dissolved in the optimum solvent, adds under the low temperature in the not optimum solvent, and L crystal formation adefovir ester is separated out in crystallization.
6. method as claimed in claim 5, wherein optimum solvent is halogenated alkanes such as chloroform, methylene dichloride, or alcoholic solvents such as methyl alcohol, ethanol, Virahol, or acetone, ethyl acetate, acetonitrile etc., preferred methylene dichloride.
7. method as claimed in claim 5, wherein not optimum solvent is alkanes such as normal hexane, hexanaphthene, sherwood oil, ethers such as ether, isopropyl ether, preferred normal hexane.
8. method as claimed in claim 5, wherein low temperature is meant-70～10 ℃.
9. contain L type adefovir ester and be mixed with the composition of one or more pharmaceutical excipients.
10. composition as claimed in claim 9 is characterized in that the composition that contains 5～150 milligrams of L type adefovir esters makes tablet.
11. composition as claimed in claim 9 is characterized in that the composition that contains 5～150 milligrams of L type adefovir esters makes capsule.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100560596C (en) * | 2007-06-28 | 2009-11-18 | 福建广生堂药业有限公司 | Preparation method and content detection method of adefovir monoester |
| 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 | A kind of saccharin adefovir dipivoxil and preparation method thereof |
| CN102153588A (en) * | 2011-03-01 | 2011-08-17 | 吉林大学 | Adefovir pharmaceutical co-crystal and preparation method thereof |
| CN101463045B (en) * | 2009-01-07 | 2011-08-31 | 合肥恒星药物研究所 | Thiophosphate nucleotide compound |
| CN102827204A (en) * | 2012-09-20 | 2012-12-19 | 中国药科大学 | Eutectic crystal form alpha of saccharin adefovir dipivoxil |
| CN103665044A (en) * | 2013-12-20 | 2014-03-26 | 悦康药业集团有限公司 | Adefovir dipivoxil compound |
| CN103709198A (en) * | 2012-09-28 | 2014-04-09 | 江苏天士力帝益药业有限公司 | Method for crystallizing adefovir dipivoxil |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100560596C (en) * | 2007-06-28 | 2009-11-18 | 福建广生堂药业有限公司 | Preparation method and content detection method of adefovir monoester |
| 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 |
| CN101463045B (en) * | 2009-01-07 | 2011-08-31 | 合肥恒星药物研究所 | Thiophosphate nucleotide compound |
| CN101544670B (en) * | 2009-05-11 | 2011-06-29 | 中国药科大学 | A kind of saccharin adefovir dipivoxil and preparation method thereof |
| CN102153588A (en) * | 2011-03-01 | 2011-08-17 | 吉林大学 | Adefovir pharmaceutical co-crystal and preparation method thereof |
| CN102153588B (en) * | 2011-03-01 | 2013-03-06 | 吉林大学 | Adefovir pharmaceutical co-crystal 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 |
| CN103709198A (en) * | 2012-09-28 | 2014-04-09 | 江苏天士力帝益药业有限公司 | Method for crystallizing adefovir dipivoxil |
| CN103665044A (en) * | 2013-12-20 | 2014-03-26 | 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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| CN100497356C (en) | 2009-06-10 |
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