CN1699385A - Crystal form of adefovir dipivoxil - Google Patents
Crystal form of adefovir dipivoxil Download PDFInfo
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- CN1699385A CN1699385A CN 200510073652 CN200510073652A CN1699385A CN 1699385 A CN1699385 A CN 1699385A CN 200510073652 CN200510073652 CN 200510073652 CN 200510073652 A CN200510073652 A CN 200510073652A CN 1699385 A CN1699385 A CN 1699385A
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Abstract
The invention relates to the crystal system of Adefovir dipivoxi, i.e. 9-[2-[bis(neovaleryoxyl) methoxy] pjosphinyl ] methoxy ] ethyl ) adenine. In addition, the invention also relates to the use of the Adefovir dipivoxi crystal system in treating liver diseases such as viral hepatitis, the pharmaceutical compositions containing the Adefovir dipivoxi crystal system and the process for preparing the Adefovir dipivoxi crystal system.
Description
The present invention is one and divides an application that the application number of original application is: 02137905.X, the applying date is: 2002.7.8, invention and created name is: " crystal formation of adefovir dipivoxil ".
Technical field
The present invention relates to two (new pentane acyloxy) methoxyl groups of 9-[2-[[] phosphinyl] methoxyl group] ethyl] the crystal formation E of VITAMIN B4.Two (new pentane acyloxy) methoxyl groups of 9-[2-[[] phosphinyl] methoxyl group] ethyl] the general adefovir dipivoxil by name of VITAMIN B4 (Adefovir dipivoxil is called for short AD).In addition, the invention still further relates to the application of E type adefovir dipivoxil in hepatic diseases such as treatment viral hepatitis, contain the pharmaceutical composition and the method for preparing E type adefovir dipivoxil of E type adefovir dipivoxil.
Background technology
In Chinese patent CN1251592A (publication number), put down in writing two (new pentane acyloxy) methoxyl groups of 9-[2-[[of the sharp special science of U.S.'s gill stock company invention] phosphinyl] methoxyl group] ethyl] the four kinds of crystal habits and the salt thereof of VITAMIN B4.Wherein, not moisture substantially and other crystallization solvent of crystallization " form 1 " AD; Crystallization " form 2 " is the dihydrate of AD, outside dewatering, does not contain other crystallization solvent usually; Crystallization " form 3 " contains 1 normal methyl alcohol approximately in lattice; Crystallization " form 4 " is for containing the AD of fumaric acid.E type adefovir dipivoxil of the present invention is different from four kinds of crystal formations of this patent any, is a kind of crystal habit of new not moisture substantially and other solvent.
In addition, costliness, inflammable harmful organic solvent such as n-butyl ether, isopropyl acetate etc. have been used in the preparation AD crystalline method that patent CN1251592A provides.
Summary of the invention
The object of the invention provides a kind of E type adefovir dipivoxil of not moisture substantially and other solvent.
Another object of the present invention provides the method for the E type adefovir dipivoxil of not moisture substantially and other solvent of preparation.
Another object of the present invention provides the pharmaceutical composition that contains E type adefovir dipivoxil.
In addition, a further object of the invention is the application of composition in hepatic diseases such as treatment viral hepatitis that contains E type adefovir dipivoxil.
The feature of E type adefovir dipivoxil:
The invention provides the E type adefovir dipivoxil of non-solventization, use the Cu-Ka radiation, its x-ray diffraction pattern is seen Fig. 1, and 2 θ that show with kilsyth basalt have absorption peak 7.4,7.8,10.1,12.4,15.2,16.4,17.3,18.0,18.6,20.1,20.4,21.3,21.6,22.3,22.8,23.4,24.4,26.1,27.5,28.5,30.1.Crystal formation " form 1 " with respect to the non-solventization of patent CN1251592A report, it typically is characterized as, and 15.2,16.4 absorption peak is arranged, and " form 1 " has 12.7,15.7,20.7 positions of absorption peak in the patent, and E type adefovir dipivoxil of the present invention does not have absorption peak.
The DSC collection of illustrative plates of E type adefovir dipivoxil of the present invention is seen Fig. 2, and its endothermic transition is at about 94 ℃, and in the patent endothermic transition of " form 1 " at about 102 ℃.
E type adefovir dipivoxil of the present invention is seen Fig. 3 with the infrared absorption pattern that the KBr compressing tablet records, and it is characterized by at about 3323cm
-1, 3166cm
-1, 1652cm
-1, 1592cm
-1There is absorption peak at the place.
The character and the pharmacodynamic study thereof of E type adefovir dipivoxil:
One, solvability: test with reference to two notes on the use of Chinese Pharmacopoeia version in 2000, method: it is an amount of that precision takes by weighing E type adefovir dipivoxil, slowly adds certain amount of solvent, and powerful jolting was 30 seconds every 5 minutes, observe the dissolving situation in 30 minutes, the results are shown in Table 1.
The solubility test of table 1 adefovir dipivoxil
| Solvent | Solute amount (g) | Quantity of solvent (ml) | Solvent/solute | Phenomenon | Conclusion |
| Methyl alcohol | ??2.08 | ??1.4 | ??0.67 | Dissolving | Very easily dissolving |
| Dehydrated alcohol | ??2.16 | ??5.6 | ??2.59 | Dissolving | Yi Rong |
| ??0.1N?HCl | ??0.48 | ??20 | ??23.8 | Dissolving | Dissolving |
| Water | ??0.11 | ??1100 | ??10000 | Insoluble | Indissoluble |
| ??0.1N?NaOH | ??0.21 | ??2100 | ??10000 | Insoluble | Indissoluble |
E type adefovir dipivoxil very easily is dissolved in methyl alcohol, is soluble in dehydrated alcohol, dissolves indissoluble in water and 0.1N NaOH solution in 0.1N HCl solution.
Two, stability
1, exposure experiments to light
E type adefovir dipivoxil raw material is evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects respectively at sampling in 5,10 days, and contrasts with 0 day result.The results are shown in Table 2.10 days X-ray diffraction figure sees Fig. 4.
Table 2 exposure experiments to light (4500 ± 500lx)
| Time (my god) | The investigation project | ||
| Outward appearance | Content (%) | Fusing point (℃) | |
| ??0 | White crystalline powder | ??98.7 | ??91.4～92.8 |
| ??5 | White crystalline powder | ??98.8 | ??91.2～92.6 |
| ??10 | White crystalline powder | ??98.6 | ??913～92.7 |
Annotate: 23～26 ℃ of temperature variation; Relative humidity variations 56%～63%
2, high temperature test
E type adefovir dipivoxil raw material is positioned in the clean vial of sealing, places 60 ℃ of thermostatic drying chambers, detect, and contrast with 0 day result respectively at sampling in 5,10 days.The results are shown in Table 3.10 days X-ray diffraction figure sees Fig. 5.
Table 3 high temperature test (60 ℃)
| Time (my god) | The investigation project | ||
| Outward appearance | Content (%) | Fusing point (℃) | |
| ??0 | White crystalline powder | ??98.7 | ??91.4～92.8 |
| ??5 | White crystalline powder | ??98.7 | ??91.4～92.9 |
| ??10 | White crystalline powder | ??98.6 | ??91.4～92.7 |
Annotate: relative humidity variations 54%～62%
3, high wet test
E type adefovir dipivoxil raw material is evenly shared to uncovered culture dish, and thickness≤5mm places room temperature (about 25 ℃), and relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, measures respectively at sampling in 5,10 days, and contrasts with 0 day result.The results are shown in Table 4.10 days X-ray diffraction figure sees Fig. 7.
The high wet test of table 4 (room temperature, relative humidity 75 ± 5%)
| Time (my god) | The investigation project | |||
| Outward appearance | Moisture absorption weightening finish (%) | Content (%) | Fusing point (℃) | |
| ??0 | White crystalline powder | ??- | ??98.7 | ??91.4～92.8 |
| ??5 | White crystalline powder | ??1.9 | ??98.6 | ??89.2～90.7 |
| ??10 | White crystalline powder | ??4.7 | ??98.6 | ??89.1～90.7 |
Annotate: 23～26 ℃ of temperature variation
4, accelerated test
E type adefovir dipivoxil raw material pack with the polyethylene film plastic bag sealing, placed 40 ± 2 ℃, relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, to place six months, respectively at 1,2, and the detection of taking a sample 3,6 the end of month, and contrast with 0 month result.The results are shown in Table 5.6 months x-ray diffraction pattern is seen Fig. 7.
Table 5 accelerated test (40 ℃, relative humidity 75%)
| Time (moon) | The investigation project | ||
| Outward appearance | Content (%) | Fusing point (℃) | |
| ??0 | White crystalline powder | ??98.7 | ??91.4～92.8 |
| ??1 | White crystalline powder | ??98.8 | ??91.4～93.2 |
| ??2 | White crystalline powder | ??98.7 | ??91.1～92.8 |
| ??3 | White crystalline powder | ??98.7 | ??91.3～92.8 |
| ??6 | White crystalline powder | ??98.6 | ??91.4～93.0 |
By The above results as can be known, the E type adefovir dipivoxil that the present invention obtains (60 ℃) in exposure experiments to light and high temperature test, outward appearance and content all do not have bigger change, and its stable in properties is described; This product its outward appearance and content in high wet test all do not have considerable change, but certain water absorbability is arranged, and its fusing point reduces.This product easily is converted into the crystallization that contains crystal water in highly humid air.So, combine with water in order to prevent this product, should seal preservation.Except that super-humid conditions, do not find the transformation of crystal formation, show to be under the dry condition that this crystal habit is stable.
Three, pharmacodynamic study
E type adefovir dipivoxil can be made into the preparation of hepatic diseases such as a kind of effective treatment animal, particularly Human virus's hepatitis, and E type adefovir dipivoxil is carried out pharmacodynamic study, and the result is as follows:
1, extracorporeal antivirus effect test: in the Bel7402 2.2.15 of hepatitis B virogene transfection cell, study the toxicity of adefovir dipivoxil pair cell and HBsAg, HBeAg and HBV DNA excretory are suppressed effect.Two batches of tests show: adefovir dipivoxil 16.0 μ g/ml begin the twice dilution, add cell cultures 8 days, pair cell median toxic concentration TC
50Be 20 μ g/ml, maximal non-toxic concentration TC
0Be 10 μ g/ml.Be 15.3 ± 6.9% to HBsAg excretory inhibiting rate during maximal non-toxic concentration; Pair cell HBeAg secretion unrestraint effect is 59.3% to the inhibiting rate of HBV DNA, suppresses the IC of HBV DNA
50Be 6.1 μ g/ml.
2, interior resisting virus test: in duck hepatitis B virus infection duck body, carry out therapeutic test, observe drug effect.Test-results shows: the duck hepatitis B virus infection duck is the 7th day oral adefovir dipivoxil after infection, 30mg/Kg group one day 2 times, inhibition effect to duck serum DHBV-DNA level after the administration in 10 days is remarkable, and three batches of test statistics are learned result all highly significant effect (P＜0.01).Infected duck serum DHBV-DNA level also there was remarkable inhibition effect, two batches of statistical procedures (P＜0.05), a collection of (P＜0.01) in the 10th day after the administration of 15mg/Kg group.But drug withdrawal suppressed % and control group contrast, only 1 batch of effect remarkable (P＜0.01) in 3 days.7.5mg/Kg organize one day 2 times 10 days to infected duck serum DHBV-DNA effect instability.Test explanation effective dose is in 1 day 2 times 10 days groups of 15-30mg/Kg.30mg/Kg did not see toxic reaction in oral 1 day 2 times 10 days.
The preparation method of E type adefovir dipivoxil:
According to document
1,2,3Report, the method for preparing adefovir dipivoxil mainly contains two kinds, and a kind of is at N, in the dinethylformamide, add 9-(2-phosphono methoxyethyl)-VITAMIN B4 (PMEA) and Chloro methyl pivalate, use N, N-dicyclohexyl-4-morpholine is made condensing agent, and triethylamine is made catalyzer, and reaction makes.Another kind is in 1-Methyl-2-Pyrrolidone, adds 9-(2-phosphono methoxyethyl)-VITAMIN B4 and Chloro methyl pivalate, and triethylamine is made condensing agent, and reaction makes.In order to improve degree of purity of production, the present invention has carried out purifying to 9-(2-phosphono methoxyethyl)-VITAMIN B4.The present invention is optimized improvement to the aftertreatment of these two kinds of methods, lower cost, improved yield, avoided using harmful organic solvent n-butyl ether, isopropyl acetate etc., and obtained new crystal E type adefovir dipivoxil, made the present invention be more suitable for suitability for industrialized production.
Method one: according to document
1,2Reported method, make 9-(2-phosphono methoxyethyl)-VITAMIN B4 earlier, use N then, dinethylformamide is made solvent, N, N-dicyclohexyl-4-morpholine is made condensing agent, and triethylamine is made catalyzer, makes the reaction of 9-(2-phosphono methoxyethyl)-VITAMIN B4 and Chloro methyl pivalate, after reacting completely, use the methylbenzene extraction product, concentrate toluene then, obtain containing the oily matter of AD.The present invention adopts and adds suitable quantity of water or add certain amount of organic solvent in the oily matter that contains AD in oily matter, stirring is dissolved in the solvent oily matter, add entry then, being stirred to a large amount of white solids separates out, filter, filter cake be dissolved in the methyl alcohol, add anhydrous magnesium sulfate drying after, evaporated under reduced pressure promptly gets E type adefovir dipivoxil.Detect with the HPLC method, purity reaches more than 98.0%.
Wherein, the water yield of adding is 1～30 times of the PMEA input amount amount of the following adding of mentioning (comprise all by weight), so that the solid of separating out stirs easily.The organic solvent that adds in oily matter has solvability preferably to adefovir dipivoxil, and as methyl alcohol, ethanol, acetone etc., the amount that adds organic solvent is generally 0.5～5 times of PMEA amount, and the amount that adds entry is generally 5～20 times that add the water yield.Siccative be anhydrous magnesium sulfate or anhydrous sodium sulphate etc. can dry methyl alcohol in moisture and not with the solid drier of adefovir dipivoxil reaction, or molecular sieve.The amount of its adding is generally 2～10 times of PMEA amount moisture complete drying in the methyl alcohol can be as the criterion.The vacuum tightness of decompression is generally-0.1MPa, also can be lower, all can reach good preparation effect.Outer bath temperature during evaporate to dryness is generally 30～60 ℃.The amount of methanol solvate is generally 1～10 times of PMEA, makes to leach the solid dissolving and be convenient to operation to get final product.
Method two: make solvent with 1-Methyl-2-Pyrrolidone, triethylamine is made condensing agent, makes the reaction of 9-(2-phosphono methoxyethyl)-VITAMIN B4 and Chloro methyl pivalate, after reacting completely, add ethyl acetate, wash with water, concentrate ethyl acetate, obtain containing the oily matter of AD.Make the method for E type adefovir dipivoxil with method one by oily matter.Purity reaches more than 98.0%.
Preparation of the present invention comprises the composition of E type adefovir dipivoxil and one or more pharmaceutical excipients, optionally, also can contain other therapeutic component.Its vehicle comprises tackiness agent, thinner, disintegrating agent, sanitas, dispersion agent, glidant and lubricant etc.Preparation of the present invention comprises tablet and capsule.These compositions can be tablet or the capsules that contains the about 5～250mg of E type adefovir dipivoxil.
Its tablet can optionally can carry out dressing or embossing to tablet by randomly forming with one or more vehicle pressing mold of granulating.Capsule too can with one or more mixed with excipients, be filled in capsule shell by granulating or not granulating and make.
Description of drawings
Fig. 1 is E type adefovir dipivoxil X-ray diffraction figure of the present invention.
Fig. 2 is E type adefovir dipivoxil differential scanning calorimetry figure of the present invention (DSC figure).
Fig. 3 is an E type adefovir dipivoxil infrared absorpting light spectra of the present invention.
Fig. 4 is 10 days X-ray diffraction figure of E type adefovir dipivoxil strong illumination of the present invention.
Fig. 5 is 60 ℃ of X-ray diffraction figure that investigate 10 days of E type adefovir dipivoxil of the present invention.
Fig. 6 is the X-ray diffraction figure that E type adefovir dipivoxil high humidity of the present invention was investigated 10 days.
Fig. 7 is that E type adefovir dipivoxil of the present invention is put the X-ray diffraction figure that investigates June in 40 ℃ of environment.
Embodiment
Embodiment 1
9-(2-phosphono methoxyethyl)-VITAMIN B4 purification process:
In the 100L reactor, with 9-(2-phosphono methoxyethyl)-VITAMIN B4 crude product 1.0Kg, add in the water of 50L, be heated to backflow, after the dissolving, keep temperature, add 100g decolorizing with activated carbon 10min, filter, put the cold analysis crystalline substance, filter, 80 ℃ of oven dry of crystallization are promptly got pure product.
The preparation of adefovir dipivoxil crystalline form E
In the 10L reactor, 9-(2-phosphono the methoxyethyl)-VITAMIN B4 0.5Kg (1.8mol) of purifying is suspended in 5L N, in the dinethylformamide, stir, add 1.044KgN, N-dicyclohexyl-4-morpholine, triethylamine 100ml and 1.382Kg (9.2mol) Chloro methyl pivalate, be warming up to 50 ℃, insulated and stirred 3 hours, elimination insolubles, filtrate is concentrating under reduced pressure under vacuum tightness-0.1Mpa, concentrated solution methylbenzene extraction (10L * 2).Reclaim under reduced pressure toluene under vacuum tightness-0.1Mpa, in remaining oily liquid, add pure water 5L, stirred 5 hours, there are a large amount of white solids to separate out, leach, it is dissolved in the 1.5L anhydrous methanol, add anhydrous magnesium sulfate 1.0Kg and stirred 2 hours, filter, mother liquor adds activated carbon 50g, in 50 ℃ of decolouring 10min, bathes 50 ℃ outward, evaporated under reduced pressure gets white solid, 50～70 ℃ of dryings 8 hours promptly get adefovir dipivoxil crystallization E 553g, yield 58%, Mp.92～94 ℃, HPLC method are surveyed content and are: 98.6%.
Embodiment 3
The preparation of adefovir dipivoxil crystalline form E
In the 10L reactor, 9-(2-phosphono the methoxyethyl)-VITAMIN B4 0.5Kg (1.8mol) of purifying is suspended in 5LN, in the dinethylformamide, stir, add 1.044KgN, N-dicyclohexyl-4-morpholine, triethylamine 100ml and 1.382Kg (9.2mol) Chloro methyl pivalate, be warming up to 50 ℃, insulated and stirred 3 hours, elimination insolubles, concentrating under reduced pressure under vacuum tightness-0.1Mpa, concentrated solution methylbenzene extraction (10L * 2).Reclaim under reduced pressure toluene under vacuum tightness-0.1Mpa, in the residue oily liquid, add ethanol 0.5L, stirring makes the oily matter dissolving, add entry 4L then, stirred 5 hours, and had a large amount of white solids to separate out, leach, it is dissolved in the 1.5L anhydrous methanol, add anhydrous magnesium sulfate 1.0Kg, dry moisture filters, mother liquor adds activated carbon 50g, in 50 ℃ of decolouring 10min, bathe 60 ℃ outward, evaporated under reduced pressure gets white solid under vacuum tightness-0.1Mpa, 50～70 ℃ of dryings 8 hours promptly get adefovir dipivoxil crystallization E 548g.Yield 57%, Mp.92～94 ℃, the HPLC method is surveyed content and is: 99.3%.
The preparation of adefovir dipivoxil crystalline form E
In the 10L reactor; 9-(2-phosphono the methoxyethyl)-VITAMIN B4 0.5Kg (1.8mol) of purifying is added in 1-methyl-2-pyrrole Lip river alkane ketone; nitrogen protection; add triethylamine 0.927Kg (9mol) then, stir adding Chloro methyl pivalate 1.377Kg (1.296mol) down, be warming up to 60 ℃; reacted 2 hours; add 6.8L ethyl acetate termination reaction, stir half an hour, filter; mother liquor washes (5L * 2) with water; reclaim under reduced pressure ethyl acetate under vacuum tightness-0.1Mpa adds pure water 5L in remaining oily liquid, stirred 4 hours; there are a large amount of white solids to separate out; leach solid, be dissolved in the 1.5L anhydrous methanol, add anhydrous magnesium sulfate 1.0Kg; dry 2 hours; filter, mother liquor adds activated carbon 50g, in 50 ℃ of decolouring 10min; 50 ℃ of outer baths; evaporated under reduced pressure gets white solid under vacuum tightness-0.1Mpa, 50～70 ℃ of dryings 8 hours, adefovir dipivoxil crystallization E 534g.Yield 56%.Mp.92～94℃。
Embodiment 5
The preparation of tablet
With several vehicle E type adefovir dipivoxil is mixed with every tablet of tablet that contains 10mg as follows.
| The supplementary material title | Prescription consumption (g/1000 sheet) | |
| Prescription 1 | | |
| Adefovir dipivoxil | ??10.0 | ??10.0 |
| Lactose | ??100.0 | ??100.0 |
| Starch | ??- | ??30.0 |
| Low-substituted hydroxypropyl cellulose | ??3.0 | ??3.0 |
| Microcrystalline Cellulose | ??3.0 | ??- |
| Talcum powder | ??6.0 | ??6.0 |
| Magnesium Stearate | ??1.0 | ??1.0 |
| 1% sodium cellulose glycolate | In right amount | In right amount |
The manufacture method that contains the tablet of E type adefovir dipivoxil is that above-mentioned vehicle and E type adefovir dipivoxil are mixed, and it is an amount of to add 1% sodium cellulose glycolate solution, makes softwood, the granulation of sieving, the wet granular oven dry, whole grain sieves, add Magnesium Stearate and talcum powder and mix compressing tablet.
Capsular preparation
With several vehicle E type adefovir dipivoxil is mixed with every capsule that contains 10mg as follows.
| The supplementary material title | Prescription consumption (g/1000 grain) | ||
| Prescription 1 | | Prescription 3 | |
| Adefovir dipivoxil | ??10.0 | ??10.0 | ??10.0 |
| Lactose | ??- | ??- | ??- |
| Starch | ??139.0 | ??- | ??- |
| Microcrystalline Cellulose | ??- | ??139.0 | ??139.0 |
| Magnesium Stearate | ??1.0 | ??1.0 | ??1.0 |
| 1% sodium cellulose glycolate | In right amount | ??- | In right amount |
The capsular manufacture method that contains E type adefovir dipivoxil is that above-mentioned vehicle and E type adefovir dipivoxil are mixed, and adds 1% sodium cellulose glycolate, makes wet granular, oven dry, and the whole grain that sieves adds Magnesium Stearate, mixes, and inserts capsule and makes.Or do not granulate, E type adefovir dipivoxil and above-mentioned mixed with excipients is even, sieve, directly insert capsule and make.
Reference:
1, Liu Xiaohui, Wang Lin, pass through treasured and etc.: Acta Pharmaceutica Sinica 1996; 31 (2): 112～117;
2, Zhang Yong, Li Xin, palace equality: Shenyang Pharmaceutical University's journal 2001; 18 (2) 95～97
3, Chinese patent, publication number CN1251592A
Claims (5)
1, a kind of crystal of adefovir dipivoxil, it is characterized in that of the crystallization of described crystalline adefovir dipivoxil for not moisture and other crystallization solvent, it uses the Cu-Ka radiation, 7.4,7.8,10.1,12.4,15.2,16.4,17.3,18.0,18.6,20.1,20.4,21.3,21.6,22.3,22.8,23.4,24.4,26.1,27.5,28.5,30.1 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent, its DSC endothermic transition is at 94 ℃, and infrared absorption pattern is about 3323cm
-1, 3166cm
-1, 1652cm
-1, 1592cm
-1There is absorption peak at the place.
2, a kind of pharmaceutical composition, it contains the defined adefovir dipivoxil crystal of claim 1 and one or more pharmaceutical excipients.
3, composition as claimed in claim 2 is characterized in that described composition is for containing 5～250mg adefovir dipivoxil crystalline tablet.
4, composition as claimed in claim 2 is characterized in that described composition is for containing 5～250mg adefovir dipivoxil crystalline capsule.
5, the defined adefovir dipivoxil crystal of claim 1 is as the application of activeconstituents in preparation treatment viral hepatitis disease medicament.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02137905 CN1211391C (en) | 2002-07-08 | 2002-07-08 | Crystal form of pifuadefuwei |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02137905 Division CN1211391C (en) | 2002-07-08 | 2002-07-08 | Crystal form of pifuadefuwei |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1699385A true CN1699385A (en) | 2005-11-23 |
| CN100488970C CN100488970C (en) | 2009-05-20 |
Family
ID=4749170
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02137905 Expired - Lifetime CN1211391C (en) | 2002-07-08 | 2002-07-08 | Crystal form of pifuadefuwei |
| CNB2005100736529A Expired - Lifetime CN100488970C (en) | 2002-07-08 | 2002-07-08 | Crystal form of adefovir dipivoxil |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02137905 Expired - Lifetime CN1211391C (en) | 2002-07-08 | 2002-07-08 | Crystal form of pifuadefuwei |
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| Country | Link |
|---|---|
| CN (2) | CN1211391C (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100383149C (en) * | 2002-11-12 | 2008-04-23 | 天津帝士力投资控股集团有限公司 | New crystalline Idedate and its composition |
| US7417036B2 (en) * | 2002-11-12 | 2008-08-26 | Tianjin Kinsly Pharmaceutical Co. Ltd. | Crystal form of adefovir dipivoxil and its preparation |
| CN1303089C (en) * | 2002-11-19 | 2007-03-07 | 天津药物研究院 | Crystalline form of Adefovir dipivoxil and preparing process thereof |
| CN100415756C (en) * | 2003-10-14 | 2008-09-03 | 沈阳药科大学 | Oxalic adefovir dipivoxil, and crystalline form and preparing method and use thereof |
| CN101193642B (en) * | 2005-06-13 | 2011-07-27 | 博瑞生物医药技术(苏州)有限公司 | Nucleotide analogue prodrug and the preparation thereof |
| CN102228463B (en) * | 2005-06-13 | 2012-12-19 | 博瑞生物医药技术(苏州)有限公司 | Tenofovir crystals |
| CN101704846B (en) * | 2009-12-03 | 2012-05-09 | 华东理工大学 | 9-(2-phosphatidyl methoxy ethyl)-adenine crystal and preparation method thereof |
-
2002
- 2002-07-08 CN CN 02137905 patent/CN1211391C/en not_active Expired - Lifetime
- 2002-07-08 CN CNB2005100736529A patent/CN100488970C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1211391C (en) | 2005-07-20 |
| CN100488970C (en) | 2009-05-20 |
| CN1396170A (en) | 2003-02-12 |
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