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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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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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| CN1634943A (en) * | 2004-11-05 | 2005-07-06 | 中国医学科学院医药生物技术研究所 | Acyclic nucleotide analogs, method for synthesis and antiviral application |
-
2010
- 2010-06-02 CN CN201010190257XA patent/CN101985454A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
| CN1634943A (en) * | 2004-11-05 | 2005-07-06 | 中国医学科学院医药生物技术研究所 | Acyclic nucleotide analogs, method for synthesis and antiviral application |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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Application publication date: 20110316 |