CN103333208B - Aldoforwe ester maleate and preparation method thereof and composition - Google Patents
Aldoforwe ester maleate and preparation method thereof and composition Download PDFInfo
- Publication number
- CN103333208B CN103333208B CN201310220097.2A CN201310220097A CN103333208B CN 103333208 B CN103333208 B CN 103333208B CN 201310220097 A CN201310220097 A CN 201310220097A CN 103333208 B CN103333208 B CN 103333208B
- Authority
- CN
- China
- Prior art keywords
- aldoforwe ester
- aldoforwe
- maleate
- maleic acid
- ester maleate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention discloses Aldoforwe ester maleate and preparation method thereof and composition. It is combined into by the mol ratio of 1:1 by Aldoforwe ester and maleic acid. The stable crystal form of Aldoforwe ester maleate of the present invention, normal condition storage is difficult for decomposing, and can keep original bioavilability, is easy to preparation. The inventive method reaction condition gentleness, is easy to control, and elementary analysis and dsc analysis result show that the purity of the Aldoforwe ester maleate of preparing is high, and impurity content is low.
Description
Technical field
The present invention relates to a kind of medicine novel crystal forms and preparation method thereof and composition, particularly Aldoforwe ester maleateAnd preparation method thereof and composition.
Background technology
Aldoforwe ester (adefovirdipivoxil, AD) is two new pentane acyloxy methyl esters of adefovirdipivoxil (Adefovir),Two (new pentane acyloxy) methoxyl groups of its chemistry 9-[2-[by name] phosphatidyl methoxy] ethyl adenine, its molecular formula isC20H32N5O8P, chemical structural formula is as follows
After Aldoforwe ester oral absorption, very soon by esterase hydrolyzed, discharge adefovirdipivoxil and bring into play drug effect, therefore, A DeGood fortune Wei ester is the prodrug of adefovirdipivoxil. Aldoforwe ester is a kind of novel Aphthovirus medicine, and it can in human bodySuppress viral DNA transcriptase and polymerase, thereby can suppress copying and transcribing of virus, HIV and hepatitis B are all hadInhibitory action also has good immunoregulation effect simultaneously.
Aldoforwe ester is developed by GileadSciences company of the U.S., makes for improving adefovirdipivoxil bioavilabilityProdrug. Aldoforwe ester, to damp and hot unstable, is easy to hydrolysis, and relevant with crystal formation. The novel crystal forms of Aldoforwe ester and salt are so farThe present is still international hot research. CN1396170 discloses E type; CN101139363 discloses M type;WO9904774 discloses anhydrous crystal type (form 1), hydrate (form 2), methylate (form 3), fumarate(form 4), Hemisulphate, hydrobromate, hydrochloride, nitrate, mesylate, esilate, α-naphthalenesulfonicacid salt,Beta-naphthalenesulfonic-acid salt, s-camsilate, succinate, maleate, ascorbate, hydrochloride; CN1528766 is openA kind of oxalates; Patent CN1396107A discloses a kind of crystal habit of not moisture and other crystallization solvent;CN1569861A discloses aspartate, taurate, gluconate, fructose hydrochlorate; CN101544670A public affairsOpen asccharin eutectic; CN102276652A discloses the another kind of crystal formation of asccharin eutectic.
Summary of the invention
The object of the invention is to Aldoforwe ester maleate and preparation method thereof and composition.
The technical solution used in the present invention is:
Aldoforwe ester maleate, is combined into by the mol ratio of 1:1 by Aldoforwe ester and maleic acid, uses Cu-K α radiation,5.1 ± 0.2,9.9 ± 0.2,10.2 ± 0.2,11.4 ± 0.2,11.9 ± 0.2 its X-ray powder diffraction at angle of diffraction 2 θ is:,14.3±0.2、15.3±0.2、16.9±0.2、18.4±0.2、21.2±0.2、21.6±0.2、22.8±0.2、25.6±0.2、Have characteristic peak at 25.8 ± 0.2,27.6 ± 0.2,30.7 ± 0.2 o'clock, its cell parameter is: α=77.536 °, β=84.298 °, γ=63.601 °, space group is P21/ c. AdefovirdipivoxilThe results of elemental analyses of ester maleate is: C (%): 47.01, N (%): 11.58, H (%): 5.79.
A kind of Pharmaceutical composition, is made up of above-mentioned Aldoforwe ester maleate and acceptable pharmaceutic adjuvant.
The method of preparing above-mentioned Aldoforwe ester maleate, comprises the steps:
1), at 0～50 DEG C, maleic acid and Aldoforwe ester are added in organic solvent; Or first maleic acid is dissolved in organic solvent,Add afterwards Aldoforwe ester;
2) fully stir, crystallization, collects gained crystalline powder, and drying under reduced pressure obtains Aldoforwe ester maleate.
Preferably, the mol ratio of maleic acid and Aldoforwe ester is (0.5～3): 1.
Preferably, organic solvent is selected from ethyl acetate, ethanol, methyl alcohol, isopropyl alcohol, acetone, acetonitrile.
Preferably, the time of stirring is no less than 30min, and the time of stirring is 30min～4h.
Preferably, when crystallization, under not higher than the environment of 40 DEG C, solvent evaporation is carried out to crystallization.
Preferably, the use amount of organic solvent is maleic acid and Aldoforwe ester gross mass 2～5 times.
The invention has the beneficial effects as follows:
The stable crystal form of Aldoforwe ester maleate eutectic of the present invention, normal condition storage is difficult for decomposing, and can keep originalBioavilability, is easy to preparation.
The inventive method reaction condition gentleness, is easy to control, and elementary analysis and dsc analysis result show the A Defu of preparationThe purity of Wei ester maleate is high, and impurity content is low.
Brief description of the drawings
Fig. 1 is the actual measurement x-ray diffractogram of powder of Aldoforwe ester maleate.
Fig. 2 is the x-ray diffractogram of powder of Aldoforwe ester maleate from mono-crystalline structures digital simulation.
Fig. 3 is the mono-crystalline structures figure of Aldoforwe ester maleate.
Fig. 4 is the three-dimensional accumulation graph of Aldoforwe ester maleate.
Fig. 5 is differential scanning calorimeter (DSC) figure of Aldoforwe ester maleate.
Fig. 6 is thermogravimetric analysis (TG) figure of Aldoforwe ester maleate.
Fig. 7 is the infrared spectrogram (IR) of Aldoforwe ester maleate.
Fig. 8 is the pharmacokinetics-time plot of Aldoforwe ester and Aldoforwe ester maleate.
Detailed description of the invention
Embodiment 1
At 50 DEG C, take 501mg Aldoforwe ester and 116mg maleic acid, add 6mL ethyl acetate stirring reaction 3 littleTime, there are a large amount of white precipitates to produce, centrifugation, solid drying under reduced pressure, after 24 hours, obtains 560mg white crystalline powderProductive rate 91%.
Embodiment 2
At 28 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL ethanol stirring reaction 2 hours, haveA large amount of white precipitates produce, centrifugation, and solid drying under reduced pressure, after 24 hours, obtains 198mg white crystalline powder, productive rate96%。
Embodiment 3
At 30 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL ethyl acetate stirring reaction 3 hours,There are a large amount of white precipitates to produce, centrifugation, solid drying under reduced pressure, after 24 hours, obtains 190mg white crystalline powder, producesRate 92%.
Embodiment 4
At 28 DEG C, take 39mg maleic acid, add after 3mL ethanol stirring and dissolving, add 167mg Aldoforwe ester to stirReact 1.5 hours, have a large amount of white precipitates to produce, centrifugation, solid drying under reduced pressure, after 24 hours, obtains 186mg whiteCrystalline powder, productive rate 90%.
Embodiment 5
At 27 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL acetone stirring reaction 2 hours, haveA large amount of white precipitates produce, centrifugation, and solid drying under reduced pressure, after 24 hours, obtains 198mg white crystalline powder, productive rate96%。
Embodiment 6
At 27 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL acetonitrile stirring reaction 2 hours, haveA large amount of white precipitates produce, centrifugation, and solid drying under reduced pressure, after 24 hours, obtains 185mg white crystalline powder, productive rate90%。
Embodiment 7
At 27 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL isopropyl alcohol stirring reaction 2 hours,There are a large amount of white precipitates to produce, centrifugation, solid drying under reduced pressure, after 24 hours, obtains 160mg white crystalline powder, producesRate 78%.
Embodiment 8
At 40 DEG C, take 167mg Aldoforwe ester and 39mg maleic acid, add 2mL ethyl acetate stirring reaction 3 hours,Filter, the volatilization of filtrate room temperature, obtains crystalline powder after 3 days, and drying under reduced pressure, after 24 hours, obtains 202mg product, productive rate98%。
Characterization data:
The Aldoforwe ester maleate that embodiment 1 is prepared is measured and is characterized, specific as follows:
Adopt BrukerD8Advance diffractometer to measure the X-ray powder diffraction figure of Aldoforwe ester maleate, condition determination asUnder: CuK α, 40kV, 40mV is light source, 0.12 ° of step-length, 10 °/min of sweep speed, 5～40 ° of sweep limits,Under room temperature, carry out. Embodiment gained X-ray powder diffraction value, with 2 θ angles, Prague, interplanar distance d and relative intensity I(withRepresent with respect to the percentage of strong ray) characterize as follows. The characterization data of embodiment 1 is in table 1, x-ray diffractogram of powderAs shown in Figure 1. Can be known corresponding in 2 θ values of the X-ray powder diffraction collection of illustrative plates that obtains Aldoforwe ester maleate by table 1Position is to there being characteristic diffraction peak.
The characterization data of the X-ray powder diffraction pattern of table 1 embodiment 1 crystal
In addition, use and measure under 293K with the AgilentTechnologiesGeminiAUltra single crystal diffractometer of graphite monochromatorThe crystal structure of Aldoforwe ester maleate. With CuK alpha ray (), collect number with ω/2 θ scan modeAccording to. Crystal structure uses SHELXS-97 program, is solved by direct method, uses SHELXL-97 program with complete matrix least squareMethod correcting principle, hydrogen atom coordinate is calculated and is added by theory. Its crystallographic parameter is as shown in the table:
*R1=Σ||Fo|-|Fc||/Σ|Fo|,wR2=[Σw(Fo 2-Fc 2)2/Σw(Fo 2)2]1/2,w=[σ2(Fo)2+(0.1(max(0,Fo 2)+2Fc 2)/3)2]-1
According to the powder diagram of mono-crystalline structures digital simulation Aldoforwe ester maleate as shown in Figure 2, with the prepared A De of actual measurementThe peak of the powder diagram (see figure 1) of good fortune Wei ester maleate is consistent, proves that the Aldoforwe ester maleate of preparation is pureSingle crystal form.
The mono-crystalline structures figure of Aldoforwe ester maleate as shown in Figure 3.
The tomograph of Aldoforwe ester maleate is shown in Fig. 4.
As shown in Figure 5, as seen from the figure, its DSC's differential scanning calorimeter figure (DSC) of Aldoforwe ester maleate absorbs heatTransformation peaks is at approximately 132.6 DEG C.
The thermal multigraph (TG) of Aldoforwe ester maleate as shown in Figure 6.
The infrared spectrogram (IR) of Aldoforwe ester maleate as shown in Figure 7, its IR(KBr, cm-1) data are3485、3056、2979、2876、2611、1907、1754、1707、1617、1557、1481、1417、1370、1314、1271、1231、1138、1059、1029、960、880、814、768、717、647、611、586、555523、481。
Pharmacokinetics-the time graph of Aldoforwe ester and Aldoforwe ester maleate as shown in Figure 8.
Crystal stability experiment
Get the prepared Aldoforwe ester maleate of embodiment 1 and carry out crystal stability test experiments. Concrete grammar is: get respectively 5The sample (each 50mg) of part material sample and 5 parts of Aldoforwe ester maleates is placed in beaker and paves, and is placed in 40 DEG C,Climatic chamber under 75%RH condition, takes out a copy of it in every 1,2,3,4,6 month and surveys PXRD, uses HPLC simultaneouslyThe remaining rate of test Aldoforwe ester. (Japanese Shimadzu company, SPD-20A detects to adopt Shimadzu high performance liquid chromatographDevice, LC-20AD pump) measure, with InertsilODS-3 post (4.6mm × 150mm, 5 μ are m) chromatographic column; With methyl alcohol0.02mol/L phosphate buffer (pH=6)=65:35 is mobile phase, and detection wavelength is 260nm, and flow velocity is 1mL/minSample size is 10 μ L. Result is as follows:
As can be seen here, the stability of Aldoforwe ester maleate is better than raw material crystal formation.
The experiment of crystal bioavilability
Get the prepared Aldoforwe ester maleate of embodiment 1 and carry out bioavailability study.
Because Aldoforwe ester is the precursor medicine of adefovirdipivoxil, Aldoforwe ester be decomposed into adefovirdipivoxil completely in vivo andPerformance drug effect, can't detect precursor medicine and monoesters in blood, therefore in blood, the content of adefovirdipivoxil reacted the life of Aldoforwe esterThing availability.
Bioavilability experimental technique: sample is suspended in to 0.5%(w/w) CMC-Na solution, being prepared into concentration is 5Mg/mL suspension, taking 50mg/kg(by adefovirdipivoxil) be dosage, after gastric infusion respectively at 10,20,40,60,120,180,240,360,480,720min gets blood 0.5mL and is placed in the centrifuge tube containing heparin, 8000rpm fromHeart 5min separated plasma, is placed in-20 DEG C of refrigerations for subsequent use.
Plasma sample pretreatment: accurately pipette 100 μ L blood plasma with liquid-transfering gun, add 400 μ L methyl alcohol, vortex 10min,Centrifugal 10min, gets supernatant, after decompressing and extracting, redissolves with 100 μ L mobile phases, and vortex 5min, centrifugal 5min, getsClear liquid carries out HPLC analysis.
The foundation of HPLC analytical method: HPLC quantitative test condition is methyl alcohol: 0.1% formic acid solution=0.03:0.47,
Flow velocity: 0.5mL/min, sample size is 20 μ L.
Data processing method: pharmacokinetic data available all adopts DAS2.0 software to calculate.
Aldoforwe ester and the Aldoforwe ester maleate average time front of blood concentration in rat body as shown in Figure 8(Aldoforwe ester (■), Aldoforwe ester maleate (●)), illustrated in 12 hours, Aldoforwe ester maleate withThe absorbing state of Aldoforwe ester is similar, and its relevant pharmacokinetic parameters table is as follows, the biological utilisation of Aldoforwe ester maleateDegree is 0.89 times of Aldoforwe ester.
Aldoforwe ester and Aldoforwe ester maleate pharmacokinetic parameters table (n=5)
In addition, after testing, Aldoforwe ester maleic acid prepared by Aldoforwe ester maleate prepared by embodiment 2-8 and embodiment 1Salt is identical. Visible, the repeatability of the inventive method is fine, can obtain stable Aldoforwe ester maleate.
Claims (7)
1. Aldoforwe ester maleate, is combined into by the mol ratio of 1:1 by Aldoforwe ester and maleic acid, and its X-ray powder diffraction is in angle of diffraction 2θFor: 5.1 ± 0.2, have characteristic peak at 9.9 ± 0.2,10.2 ± 0.2,11.4 ± 0.2,11.9 ± 0.2,14.3 ± 0.2,15.3 ± 0.2,16.9 ± 0.2,18.4 ± 0.2,21.2 ± 0.2,21.6 ± 0.2,22.8 ± 0.2,25.6 ± 0.2,25.8 ± 0.2,27.6 ± 0.2,30.7 ± 0.2 o'clock, its cell parameter is：a=9.5949?，b=10.1010?,c=17.5958?,α=77.536°，β=84.298°，γ=63.601 °, space group isP21/ c 。
2. a Pharmaceutical composition, is made up of Aldoforwe ester maleate claimed in claim 1 and acceptable pharmaceutic adjuvant.
3. the method for preparation Aldoforwe ester maleate claimed in claim 1, comprises the steps:
1), at 0～50 DEG C, maleic acid and Aldoforwe ester are added in organic solvent; Or first maleic acid is dissolved in organic solvent, add afterwards Aldoforwe ester;
2) fully stir, crystallization, collects gained crystalline powder, and drying under reduced pressure obtains Aldoforwe ester maleate;
Wherein, organic solvent is selected from ethyl acetate, ethanol, methyl alcohol, isopropyl alcohol, acetone, acetonitrile.
4. method according to claim 3, is characterized in that: the mol ratio of maleic acid and Aldoforwe ester is (0.5～3): 1.
5. according to the method described in claim 3 or 4, it is characterized in that: the time of stirring is no less than 30min.
6. method according to claim 5, is characterized in that: the time of stirring is 30min～4h.
7. according to the method described in claim 3 or 4, it is characterized in that: the use amount of organic solvent is maleic acid and Aldoforwe ester gross mass 2～5 times.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310220097.2A CN103333208B (en) | 2013-06-04 | 2013-06-04 | Aldoforwe ester maleate and preparation method thereof and composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310220097.2A CN103333208B (en) | 2013-06-04 | 2013-06-04 | Aldoforwe ester maleate and preparation method thereof and composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103333208A CN103333208A (en) | 2013-10-02 |
| CN103333208B true CN103333208B (en) | 2016-05-11 |
Family
ID=49241427
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310220097.2A Expired - Fee Related CN103333208B (en) | 2013-06-04 | 2013-06-04 | Aldoforwe ester maleate and preparation method thereof and composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103333208B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541701A (en) * | 2015-12-11 | 2016-05-04 | 吉林大学珠海学院 | Pharmaceutical cocrystal of deferiprone with maleic acid as precursor, and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251592A (en) * | 1997-07-25 | 2000-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog composation |
| CN1763056A (en) * | 1997-07-25 | 2006-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog compound |
| KR20110006424A (en) * | 2009-07-14 | 2011-01-20 | 주식회사 셀트리온제약 | Pharmaceutical composition comprising adefovir dipivoxil and acetyl-l-carnitine |
| KR20120049039A (en) * | 2010-11-08 | 2012-05-16 | (주) 성운파마코피아 | Preparation method for adefovir dipivoxil |
-
2013
- 2013-06-04 CN CN201310220097.2A patent/CN103333208B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1251592A (en) * | 1997-07-25 | 2000-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog composation |
| CN1763056A (en) * | 1997-07-25 | 2006-04-26 | 吉尔利德科学股份有限公司 | Nucleotide analog compound |
| KR20110006424A (en) * | 2009-07-14 | 2011-01-20 | 주식회사 셀트리온제약 | Pharmaceutical composition comprising adefovir dipivoxil and acetyl-l-carnitine |
| KR20120049039A (en) * | 2010-11-08 | 2012-05-16 | (주) 성운파마코피아 | Preparation method for adefovir dipivoxil |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103333208A (en) | 2013-10-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8933114B2 (en) | Polymorphic forms of asenapine maleate and processes for their preparation | |
| CN102964384B (en) | Adefovir dipivoxil gallic acid eutectic, and preparation method and composition thereof | |
| CN104356072A (en) | 5-fluorouracil drug eutectic crystal and preparation method thereof | |
| CN105164105A (en) | Dipyrromethene crystal and method for manufacturing same | |
| EP2925753A1 (en) | Novel polymorphs of azilsartan medoxomil | |
| US9169257B2 (en) | Crystal forms of adefovir dipivoxil and processes for preparing the same | |
| CN103333208B (en) | Aldoforwe ester maleate and preparation method thereof and composition | |
| CN108329308B (en) | Solid form of dihydropyrimidine compound and preparation method thereof | |
| CN107043376A (en) | A kind of Li Gelieting novel crystal forms and preparation method thereof | |
| WO2014036865A1 (en) | Method for preparing fingolimod mucate and crystal thereof and application of fingolimod mucate and crystal thereof | |
| CN110305131A (en) | Li Gelieting novel crystal forms and preparation method thereof | |
| CN102464639A (en) | Novel crystal forms of mycophenolate sodium and preparation method thereof | |
| CN102428098B (en) | Novel solid materials of {[2s, 5r,8s,11s)-5-benzyl-11-(3-guanidino-propyl)-8-isopropyl-7-methyl-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaaza-cyclopentadec-2-yl]-acetic acid} and methods for obtaining them | |
| CN108794342A (en) | Ammonium carboxylate salt compound, its crystal form, amorphous substance and preparation method thereof | |
| CN114790210A (en) | Crystal form of nucleoside compound salt | |
| CN102485229B (en) | antiviral drugs | |
| CN103588724A (en) | Febuxostat crystal form A and preparation method thereof | |
| CN105859748B (en) | Polycyclic compound sodium salt and its polymorphic, preparation method and application | |
| US9567298B2 (en) | Crystal forms of azetidinone compounds and preparing methods thereof | |
| CN112898346A (en) | Water-soluble polycyclic compound, and pharmaceutical composition and application thereof | |
| CN100516078C (en) | Adefovir dipivoxil CHARIOTEER crystallographic form and preparation method thereof | |
| CN105315266A (en) | Crystal forms of 1-{2-fluoro-4-[5-(4-isobutyl phenyl)-1,2,4-oxadiazole-3-yl]-benzyl}-3-azetidinecarboxylic acid | |
| CN115417812B (en) | Axitinib-nicotinamide eutectic crystal and preparation method and application thereof | |
| CN105461637A (en) | Macitentan crystal form and preparation method thereof | |
| CN105228988A (en) | Crystal of bent Ge Lieting hemisuccinic acid salt and preparation method thereof and pharmaceutical composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160511 Termination date: 20200604 |