CN101985454A - Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof - Google Patents
Novel crystal form of tenofovir ester maleate, preparation method and pharmaceutical application thereof Download PDFInfo
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- CN101985454A CN101985454A CN201010190257XA CN201010190257A CN101985454A CN 101985454 A CN101985454 A CN 101985454A CN 201010190257X A CN201010190257X A CN 201010190257XA CN 201010190257 A CN201010190257 A CN 201010190257A CN 101985454 A CN101985454 A CN 101985454A
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- tenofovir disoproxil
- ethyl acetate
- maleate
- new crystal
- temperature
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- 239000013078 crystal Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 11
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 9
- 229960004556 tenofovir Drugs 0.000 title abstract description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000002148 esters Chemical class 0.000 title abstract description 3
- -1 tenofovir maleate Chemical class 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- VCMJCVGFSROFHV-VIEYUMQNSA-N [[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(propan-2-yloxycarbonyloxymethoxy)phosphoryl]oxymethyl propan-2-yl carbonate (Z)-but-2-enedioic acid Chemical compound OC(=O)\C=C/C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-VIEYUMQNSA-N 0.000 claims description 25
- 229950010608 tenofovir disoproxil maleate Drugs 0.000 claims description 25
- 239000007787 solid Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000006260 foam Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000012452 mother liquor Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 3
- 150000003839 salts Chemical group 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000005755 formation reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229960004693 tenofovir disoproxil fumarate Drugs 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
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- XNYBQIJQJLOUNI-UHFFFAOYSA-N C(C)(C)OC(C)C.C(=O)=O Chemical compound C(C)(C)OC(C)C.C(=O)=O XNYBQIJQJLOUNI-UHFFFAOYSA-N 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 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 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical class N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Abstract
The invention provides a novel crystal form of a tenofovir maleate, a preparation method and a pharmaceutical application thereof. The novel crystal form in a salt form facilitates the more stable presence of the tenofovir ester. A study on the stability of the crystal form shows that the novel crystal form of the tenofovir ester maleate is more stable than that reported in previous documents and is excellent in flowability. The novel crystal form tremendously improves the stability during industrial production and flowability and compressibility during preparation, and greatly meets the needs of industrial production.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to two (pivaloyl oxygen methyl) the phosphono methoxy-propyls of (R)-9-[2-] the VITAMIN B4 maleate (English name is 9-[2-(R)-[bis[pivaloyloxymethoxy]-phosphinoylmethoxy] propyl] adenine maleate, hereinafter to be referred as the tenofovir disoproxil maleate) new crystal, its preparation method and the application in the preparation medicine thereof.
Background technology
Fumaric acid tynofovir ester (tenofovir diSOProxilfumarate), chemistry its structural formula of (R)-[[2-(6-amino-9H-purine-9-yl)-1-methyl ethoxy] methyl] phosphonic acids diisopropyl oxygen carbonyl oxygen base methyl esters fumarate by name is suc as formula shown in one, it is the nucleotide reverse transcriptase inhibitors of U.S. Gilead Sciences company research and development, it is the prodrug of tynofovir (PMPA), its structural formula is suc as formula shown in two, calendar year 2001 goes on the market in the U.S. first, clinically be mainly used in treatment human immunodeficiency virus (HIV) and infect [2], and can with other antiretroviral drugs couplings.2008, FDA ratified its new indication that is used for HBV again.
Formula one
Formula two
But, therefore manyly improve its stability by methods such as salifies because there is the problem of aspect such as stability in tenofovir disoproxil.Research about tenofovir disoproxil salt aspect at present mainly contains: U.S. Pat 5922695 has been reported a kind of crystal formation I; Chinese patent, application number are 200710014625.3 to have reported crystal form A and B; PCT patent, application number are that PCT/IN2005/000248 has also reported a kind of new crystal, and these files are all confirmed the new crystal of invention separately by analytical technology.Though above-mentioned research has some improvement aspect stable, but for industrialized production technology, still the problem that has stable aspect, and because the large usage quantity of tenofovir ester formulation Central Plains material medicine is 300mg, the flowability problem of bulk drug also becomes a factor of restriction industrialized production in preparation process.
Summary of the invention
The object of the present invention is to provide a kind of new crystal that is more suitable for the tenofovir disoproxil maleate of industrialized production demand.
Our company carries out crystallization by the one-tenth salt form of tenofovir disoproxil maleate, the new crystal of finding new one-tenth salt form is different with crystal formation in the past, help more stably existing of tenofovir disoproxil, tenofovir disoproxil maleate structural formula is as shown in the formula shown in three.
Formula three
Target product is carried out crystal formation and the structure that powder X-ray diffraction and nuclear magnetic resonance spectroscopy are confirmed product, find that the crystal formation of this new crystal and report in the past is different, that confirms that my company produces is tenofovir disoproxil maleate new crystal.
Another object of the present invention is to provide a kind of preparation method of new crystal of tenofovir disoproxil maleate.
The preparation process of the new crystal of tenofovir maleate is as follows,
With PMPA; the chloromethyl tert-butyl ester; triethylamine and N-Methyl pyrrolidone mix under nitrogen protection and heat; temperature of charge is dropped to room temperature, add ethyl acetate, water stirs; separatory; water continues with the ethyl acetate back extraction once, and combined ethyl acetate back mutually washs once with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying dewaters.Be not higher than under 50 ℃ the temperature, vacuum boils off organic solvent, obtains viscous yellow oil, crosses column purification and gets white foam shape solid.
With white foam shape solid, toxilic acid, ethanol are heated to filtered while hot after 60 ℃ of stirrings.Mother liquor be not higher than under 50 ℃ the temperature, and vacuum boils off organic solvent and gets little yellow oil.Dissolve oily matter with hot ethyl acetate, mix postcooling to room temperature, add crystal seed, be positioned over 10 ℃, 24 hours after-filtration with the amount of ethyl acetate washing, get white solid, are target product.
More specifically, crystallisation process is the tenofovir disoproxil solid with the white foam shape, toxilic acid, ethanol is heated to filtered while hot after the 40-60 ℃ of stirring, and mother liquor is under 30-50 ℃ temperature, and vacuum boils off organic solvent and gets little yellow oil, with 30-60 ℃ of hot ethyl acetate dissolving oily matter, mix postcooling to room temperature, add crystal seed, be positioned over 10-15 ℃, 12-24 hour after-filtration, with the amount of ethyl acetate washing, get white solid, be target product.
Target product is carried out crystal formation and the structure that powder X-ray diffraction and nuclear magnetic resonance spectroscopy are confirmed product, find that the crystal formation of this new crystal and report in the past is different, that confirms that my company produces is tenofovir disoproxil maleate new crystal.(powder X-ray diffraction and nuclear magnetic resonance spectroscopy data are seen embodiment 1 and accompanying drawing 1-3)
A further object of the present invention is to provide a kind of pharmaceutical composition that contains the new crystal of tenofovir disoproxil maleate.
We have carried out solvability and stability study to this new crystal of tenofovir disoproxil maleate: solvability and the crystal formation of bibliographical information was suitable in the past; By stability number according to one's analysis, find our new crystal of the tenofovir disoproxil maleate of preparation now, have better stability than the crystal formation of bibliographical information in the past.
And we find that also this new crystal has good flowability in preparation process, detect with the fixed funnel method, and the slope of repose is less than 30 degree, and the measurement result favorable reproducibility.Flowability, compressibility that this has greatly improved slice, thin piece in the preparation process have satisfied need of industrial production greatly.
Therefore can also can make up as required with new crystal and one or more pharmaceutical excipients and the carrier combinations of tenofovir disoproxil maleate, make the multiple preparation that is fit to clinical needs with other therapeutic component.
A further object of the present invention is to provide the new crystal of tenofovir disoproxil maleate to treat HIV or/and the application in the HBV medicine in preparation.The new crystal of tenofovir disoproxil maleate is suitable with other crystal formations aspect active.
Description of drawings
The X powder diffraction figure of the new crystal that Fig. 1 embodiment 1 obtains
The nuclear magnetic resonance spectrum of the new crystal that Fig. 2 embodiment 1 obtains
The enlarged view at peak in Fig. 3 Fig. 2 nuclear magnetic resonance spectrum
Embodiment
Two (pivaloyl oxygen methyl) the phosphono methoxy-propyls of embodiment 1 (R)-9-[2-] the synthetic and crystallization process of VITAMIN B4 (tenofovir disoproxil) purifies
With PMPA (5g), the chloromethyl tert-butyl ester (13.79mL), triethylamine (7.64mL) and N-Methyl pyrrolidone (19 gram) mix under nitrogen protection and are heated to 60 ± 3 ℃ (being no more than 65 ℃).After 2 hours, TLC (methylene chloride=15/1) shows that raw material disappears.Temperature of charge is dropped to room temperature (25 ± 2 ℃), add ethyl acetate (50mL), water (30mL) stirred 30 minutes, separatory, water continues with ethyl acetate (50mL) back extraction once, combined ethyl acetate back mutually washs once with saturated sodium-chloride water solution (20mL), and anhydrous sodium sulfate drying dewaters.Be not higher than under 50 ℃ the temperature, vacuum boils off organic solvent, obtains viscous yellow oil 10g, crosses column purification and gets white foam shape solid (3g).
With white foam shape solid (3g), toxilic acid (0.34g), ethanol (15mL) are heated to 60 ℃ and stir filtered while hot after 1 hour.Mother liquor be not higher than under 50 ℃ the temperature, and vacuum boils off organic solvent and gets little yellow oil (3.4g).With hot EA (250mL, about 50 ℃ of temperature) dissolving oily matter, mix postcooling to room temperature, add crystal seed, be positioned over 10 ℃, 24 hours after-filtration with the amount of ethyl acetate washing, get white solid.
Target product is carried out crystal formation and the structure that the analysis of X-ray powder diffraction (collection of illustrative plates is seen Fig. 1) and nucleus magnetic resonance (collection of illustrative plates is seen Fig. 2,3) is confirmed product, the crystal formation of finding this new crystal and report in the past is different, and that confirms that my company produces is tenofovir disoproxil maleate new crystal.
It uses Cu-Ka radiating X-ray powder diffraction data as follows:
Detected result
Peak tabulation (Peak List)
Pos.[°2Th.] Height[cts] FWHM[°2Th.] d-spacing
Rel.Int.[％]
5.0085 38279.12 0.0974 17.64409 100.00
9.8551 7376.27 0.1299 8.97521 19.27
10.6192 3937.81 0.1948 8.33112 10.29
11.1672 11974.32 0.1299 7.92348 31.28
12.2039 6020.10 0.0974 7.25259 15.73
12.6268 5511.11 0.1299 7.01062 14.40
12.8829 4471.88 0.0974 6.87182 11.68
14.5198 4319.12 0.1624 6.10063 11.28
15.0131 1614.23 0.1299 5.90124 4.22
15.6239 3449.58 0.1624 5.67190 9.01
16.3991 10142.20 0.1624 5.40550 26.50
17.0480 5422.60 0.1948 5.20116 14.17
17.8750 30713.54 0.2273 4.96236 80.24
18.2628 20591.11 0.1948 4.85785 53.79
18.4469 14665.91 0.0649 4.80979 38.31
19.0591 3403.54 0.1299 4.65665 8.89
19.8331 11230.14 0.1624 4.47662 29.34
20.1407 13344.70 0.1624 4.40895 34.86
20.5859 23372.03 0.1948 4.31459 61.06
21.2819 4245.81 0.1948 4.17504 11.09
21.7833 2886.09 0.1948 4.08007 7.54
22.4400 3148.16 0.1948 3.96212 8.22
22.8332 4172.82 0.1624 3.89477 10.90
23.0940 3346.39 0.0974 3.85137 8.74
24.1772 3331.34 0.1299 3.68122 8.70
24.4638 3869.30 0.1299 3.63875 10.11
25.1281 20880.70 0.1948 3.54404 54.55
25.8285 4826.17 0.1624 3.44950 12.61
26.4542 3369.49 0.1948 3.36932 8.80
26.8502 2005.86 0.1299 3.32051 5.24
27.5555 5879.19 0.1948 3.23710 15.36
28.2525 2352.89 0.1624 3.15881 6.15
28.7553 3102.06 0.1624 3.10471 8.10
28.9083 3070.97 0.0974 3.08863 8.02
29.2568 3750.69 0.1299 3.05262 9.80
29.8870 9396.28 0.1948 2.98967 24.55
30.3560 2790.15 0.1624 2.94455 7.29
31.3280 1859.68 0.1948 2.85537 4.86
32.4539 1603.69 0.1624 2.75884 4.19
33.0558 1896.44 0.2598 2.70997 4.95
33.6445 2045.59 0.1624 2.66388 5.34
34.4961 1902.12 0.1948 2.60004 4.97
34.8130 1893.33 0.1299 2.57710 4.95
35.5327 1380.25 0.1948 2.52654 3.61
36.4721 1365.58 0.3247 2.46359 3.57
37.3949 1766.55 0.2273 2.40489 4.61
38.2621 891.08 0.2273 2.35236 2.33
39.2014 961.69 0.3247 2.29813 2.51
40.7701 1281.40 0.2922 2.21326 3.35
41.9121 781.87 0.1948 2.15555 2.04
42.2892 707.19 0.5196 2.13720 1.85
43.8742 733.62 0.3897 2.06360 1.92
44.5984 707.41 0.2598 2.03176 1.85
Its H
1-NMR spectrum data are as follows:
H
1-NMR(CDCl
3)：8.347(1H，s，H-8)7.969(1H，s，H-2)5.819(2H，s，NH2)5.676(4H，m，CH2OP)4.360(1H，dd，J＝14.4，2.8，H-1)4.132(1H，dd，J＝14.4，7.2，H-1’)3.933(1H，，m，H-2)3.898(1H，dd，J＝14.0，8.8，H-4)3.677(1H，dd，J＝14.0，9.2，H-4’)1.238(3H，D，J＝6.0，CH3)1.215(18H，d，J＝6.0，CH3)
With white foam shape solid (3g), toxilic acid (0.34g), ethanol (20mL) are heated to 50 ℃ and stir filtered while hot after 1 hour.Mother liquor is under 30 ℃ temperature, and vacuum boils off organic solvent and gets little yellow oil (3.3g).With hot ethyl acetate (200mL, about 50 ℃ of temperature) dissolving oily matter, mix postcooling to room temperature, add crystal seed, be positioned over 10 ℃, 12 hours after-filtration with the amount of ethyl acetate washing, get white solid.
Embodiment 3
With white foam shape solid (3g), toxilic acid (0.39g), ethanol (20mL) are heated to 60 ℃ and stir filtered while hot after 1 hour.Mother liquor is under 30 ℃ temperature, and vacuum boils off organic solvent and gets little yellow oil (3.3g).With hot ethyl acetate (200mL, about 40 ℃ of temperature) dissolving oily matter, mix postcooling to room temperature, add crystal seed, be positioned over 10 ℃, 18 hours after-filtration with the amount of ethyl acetate washing, get white solid.
The preparation of embodiment 4 tenofovir ester formulations
Tenofovir disoproxil maleate new crystal
(in tenofovir disoproxil) 300g
Lactose 140g
Microcrystalline Cellulose 100g
Croscarmellose sodium 18g
Magnesium Stearate 5g
Make 1000, every contains activeconstituents 300mg.
Its preparation method is as follows: with tenofovir disoproxil maleate new crystal, earlier lactose, Microcrystalline Cellulose are mixed in mixing tank, add entry and form wet granular, grind, dry in fluidized-bed, add crosslinked sodium carboxymethylcellulose pyce then, Magnesium Stearate mixes, and compressing tablet gets final product.
The test example
The tenofovir disoproxil maleate new crystal that we prepare embodiment 1 with prepare tenofovir disoproxil fumarate crystal according to US 5922695 and carried out relevant dissolubility test and stability study, and and the crystal formation of other bibliographical information compare, as follows
Stability analysis
Table 1 high temperature test (60 ℃)
Annotate: relative humidity variations 54%-62%
High wet test
Sample is evenly shared to uncovered culture dish, and thickness≤5mm places room temperature (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 2.
The high wet test of table 2 (room temperature, relative humidity 75 ± 5%)
Annotate: temperature variation 23-26 ℃
Accelerated test
Sample 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 3 months, respectively at 1,2, and the detection of taking a sample 3 the end of month, and contrast with 0 month result.The results are shown in Table 3.
Table 3 accelerated test (40 ℃, relative humidity 75%)
By The above results as can be known, the new crystal of all tenofovir disoproxil maleate of obtaining of the present invention has better stability.
Claims (6)
1. the new crystal of a tenofovir disoproxil maleate, structural formula is as follows, it is characterized in that, its at its X-ray powder diffraction figure 10.6 ± 0.1,12.2 ± 0.1,15.0 ± 0.1,16.4 ± 0.1,17.0 ± 0.1,18.2 ± 0.1,20.5 there is characteristic peak ± 0.1,21.3 ± 0.1,22.4 ± 0.1 2 θ positions.
2. method for preparing the new crystal of tenofovir disoproxil maleate as claimed in claim 1, it is characterized in that, its step is as follows, with the tenofovir disoproxil solid of white foam shape, toxilic acid, ethanol are heated to filtered while hot after 60 ℃ of stirrings, mother liquor be not higher than under 50 ℃ the temperature, vacuum boils off organic solvent and gets little yellow oil, dissolves oily matter with hot ethyl acetate, mixes the postcooling crystallization.
3. method for preparing the new crystal of tenofovir disoproxil maleate as claimed in claim 1, it is characterized in that, the following tenofovir disoproxil solid of its step with the white foam shape, toxilic acid, ethanol is heated to filtered while hot after the 40-60 ℃ of stirring, mother liquor is under 30-50 ℃ temperature, vacuum boils off organic solvent and gets little yellow oil, with 30-60 ℃ of hot ethyl acetate dissolving oily matter, mixes postcooling to room temperature, add crystal seed, be positioned over 10-15 ℃, 12-24 hour after-filtration washs with amount of ethyl acetate, get white solid, be target product.
4. as the method for the new crystal of claim 2 or 3 described preparation tenofovir disoproxil maleate; wherein the tenofovir disoproxil solid of white foam shape can make by following steps: with PMPA; the chloromethyl tert-butyl ester; triethylamine and N-Methyl pyrrolidone mix under nitrogen protection and heat; temperature of charge is dropped to room temperature; add ethyl acetate; water stirs; separatory; water continues with the ethyl acetate back extraction once; combined ethyl acetate back mutually washs once with saturated sodium-chloride water solution, and anhydrous sodium sulfate drying dewaters.Be not higher than under 50 ℃ the temperature, vacuum boils off organic solvent, obtains viscous yellow oil, crosses column purification and gets white foam shape solid.
5. a pharmaceutical composition is characterized in that, it contains the new crystal of tenofovir disoproxil maleate as claimed in claim 1.
6. the new crystal of tenofovir disoproxil maleate according to claim 1, the application in preparation treatment HIV and HBV medicine.
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| CN103172533A (en) * | 2011-12-20 | 2013-06-26 | 博瑞生物医药技术(苏州)有限公司 | New crystal form of Aliskiren hemifumarate, and preparation method and use thereof |
| WO2013132314A1 (en) * | 2012-03-05 | 2013-09-12 | Laurus Labs Private Limited | Tenofovir phosphate, processes for the preparation and pharmaceutical composition thereof |
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| WO2014184802A1 (en) * | 2013-04-22 | 2014-11-20 | Mylan Laboratories Ltd | Novel polymorph of tenofovir disoproxil maleate |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103172533A (en) * | 2011-12-20 | 2013-06-26 | 博瑞生物医药技术(苏州)有限公司 | New crystal form of Aliskiren hemifumarate, and preparation method and use thereof |
| CN103172533B (en) * | 2011-12-20 | 2016-05-04 | 博瑞生物医药（苏州）股份有限公司 | Novel crystal forms of a kind of Aliskiren hemifumarate and its production and use |
| WO2013132314A1 (en) * | 2012-03-05 | 2013-09-12 | Laurus Labs Private Limited | Tenofovir phosphate, processes for the preparation and pharmaceutical composition thereof |
| CN103360425A (en) * | 2012-04-01 | 2013-10-23 | 安徽贝克联合制药有限公司 | Synthesis method of tenofovir disoproxil and fumarate thereof |
| CN103626803A (en) * | 2012-08-23 | 2014-03-12 | 四川海思科制药有限公司 | Solid of tenofovir disoproxil, and preparation method and application thereof |
| US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
| WO2014184802A1 (en) * | 2013-04-22 | 2014-11-20 | Mylan Laboratories Ltd | Novel polymorph of tenofovir disoproxil maleate |
| AU2014266812B2 (en) * | 2013-04-22 | 2019-10-03 | Mylan Laboratories Ltd | Novel polymorph of Tenofovir disoproxil maleate |
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