CN103880799A - New crystal forms of sodium mycophenolate and preparation method thereof - Google Patents
New crystal forms of sodium mycophenolate and preparation method thereof Download PDFInfo
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- CN103880799A CN103880799A CN201410153692.3A CN201410153692A CN103880799A CN 103880799 A CN103880799 A CN 103880799A CN 201410153692 A CN201410153692 A CN 201410153692A CN 103880799 A CN103880799 A CN 103880799A
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- sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
- C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to new crystal forms MK1, MK2 and MK3 of sodium mycophenolate and a preparation method thereof.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specially new crystal of Mycophenolate Sodium and preparation method thereof.
Background technology
Mycophenolate Sodium (Mycophenolate Sodium) chemical name: E-4-methyl-6-(1, the different benzo furan of 3-dihydro-7-methyl-4-hydroxyl-6-methoxyl group-3-oxo-5-is fed base)-4-hexenoic acid sodium, nineteen sixty end, Elililly discloses it has restraining effect to malignant cell growth.Its chemical structural formula is:
Novartis has developed a kind of enteric coating preparation of Mycophenolate Sodium, is called Myfortic, is a kind of novel immunosuppressor.Mycophenolic Acid can form a sodium or disodium salt, south african patent NO.6804959 has described the preparation of Mycophenolic Acid one sodium and disodium, after the sodium methylate of one molar equivalent reacts in the mixed solvent of methyl alcohol and chloroform with Mycophenolic Acid, Mycophenolic Acid one sodium can be by using Skellysolve A precipitate and separate, the preparation of corresponding disodium salt has also been described simultaneously, in this case, the sodium methylate of two molar equivalents is joined in Mycophenolic Acid benzene-chloroform mixed solvent to the acetone/water crystallization of the material after evaporation.
The synthetic route of WO97/38689 with in south african patent NO.6804959, describe identical, compound can by acetone/ethanol recrystallization with crystallization pattern obtain (m.p.189-191 ℃).
Polymorphic form can produce the thermal behavior that is different from amorphous substance or another kind of polymorphic form, and thermal behavior can be passed through for example technical measurement of capillary melting point, thermogravimetric analysis (TGA) and dsc (DSC) in laboratory.And can be used for distinguishing some polymorphic form.Specific polymorphic form also can produce different spectral qualities, and these character can be passed through powder X-ray crystallography, solid-state C-NMR spectrometry and infrared spectrometry and detect.
WO2004/020426 discloses and has passed through Mycophenolic Acid or its ammonium salt or dibenzyl-amine salt and C
2-C
10carboxylic acid sodium salt reaction, prepares Mycophenolate Sodium.By Mycophenolic Acid being converted into ammonium salt with ammonia react.This compound and acetic acid sodium reaction are obtained to the sodium salt of Mycophenolic Acid.
WO2004/064806 discloses the other polymorphic of Mycophenolate Sodium and Mycophenolic Acid.
South african patent No.68/4959 provides the embodiment for preparing Mycophenolic Acid one sodium salt.The absolute methanol solution of sodium methylate is joined in the chloroformic solution of Mycophenolic Acid, then by adding Skellysolve A that one sodium salt is separated out, and filter and collect and vacuum-drying.
Acta Chrtystallographica Sect.C, (2000), C56,432-433 has described the another kind of method of preparing Mycophenolic Acid one sodium.Sodium methylate processing by the methanol solution of commercially available Mycophenolic Acid with monovalent.After stirring at room temperature 1 hour, solvent vacuum-evaporation is extremely dry.The fusing point of product is 463K (190 ℃).Water/ethyl acetate solution is evaporated and is cooled to room temperature from 323K, make single crystal growing.The crystalline structure (M2 crystal formation) of the Mycophenolate Sodium producing of being measured by single crystal diffractometer has also been described.
PCT97/38689 has described Mycophenolic Acid sodium salt known in south african patent, has also described the method that obtains a sodium salt of crystallized form by acetone/ethanol recrystallization, and its fusing point is 189-191 ℃; J.Med.Chem. (1996), 39,1236-1242 has described in room temperature, the moles of sodium ethoxide such as uses to process Mycophenolic Acid ethanolic soln, and stirs vacuum evaporating solvent 30 minutes;
J.Pharm.Sciences (1970), 59 (8), 1157-1159 declares that Mycophenolic Acid one sodium can, by regulate Mycophenolic Acid soup compound to form to pH7-8 with sodium hydroxide, not provide physical data.
WO2006/012385 has described the Mycophenolic Acid one sodium crystallized form that comprises called after M1, M3, M4, M5, M6, M7, M8, M9, M10, M11, M15, M16, M17, M18, M19, M20, M21, M22, M26, M27 and M28 crystal formation, amorphous Mycophenolic Acid one sodium M12, crystallization Mycophenolic Acid two sodium crystal D1 and D2 and preparation thereof.
As the crystallization Mycophenolate Sodium of M1 crystal formation is characterized in that having 4.7,6.6,8.2,11.2,15.6,21.5 and 23.4 ± 0.2 powder X-ray RD collection of illustrative plates of spending 2-θ peaks.Its preparation method is by the C of Mycophenolic Acid
1-C
4alcoholic solution mixes with alkali and sodium source solution; By cooling this mixture, crystallized form is separated out, and before another kind of crystallized form, reclaim this crystallized form changing into.
Summary of the invention
The present invention includes the Mycophenolic Acid one sodium crystallized form of called after MK1, MK2, MK3 crystal formation, and preparation method thereof.The present invention also comprises the medicinal compositions of the arbitrary form that comprises Mycophenolic Acid sodium crystal of the present invention.
The crystal form M K1 of Mycophenolate Sodium of the present invention, its X-ray powder diffraction has diffracted ray at following 2-θ angle: 4.48,12.02,13.37,17.23 and 17.85 ± 0.2 degree, wherein the diffracted ray of intensity maximum is spent (Fig. 1) corresponding to 2-θ angle 13.37.Crystal form M K2, its X-ray powder diffraction has diffracted ray at following 2-θ angle: 5.2,8.9,20.54,26.38,30.22,31.86,32.3,39.2,43.30 and 43.7 degree ± 0.2 degree, wherein the diffracted ray of intensity maximum is spent (Fig. 2) corresponding to 2-θ angle 26.38.Crystal form M K3, its X-ray powder diffraction has diffracted ray at following 2-θ angle: 4.94,5.85,16.56,17.18,19.72,21.98 ± 0.2 degree, wherein the diffracted ray of intensity maximum is spent (Fig. 3) corresponding to 2-θ angle 4.94.
Crystal form X-ray powder diffraction analysis of Mycophenolate Sodium of the present invention is under envrionment temperature and ambient moisture, through the Cu K of Japanese Rigaku D/max-2400X-ray powder diffraction instrument
α 1=1.54056A has measured." envrionment temperature " when X-ray powder diffraction is measured is generally 0～40 ℃; " ambient moisture " is generally 30%～80% relative humidity.
The preparation method of the crystal formation of Mycophenolate Sodium of the present invention, for making Mycophenolate Mofetil in alcohols, esters solvent and at alkali or the rear crystallization of sodium source reaction, filters, and drying under reduced pressure obtains; Alcoholic solvent is as methyl alcohol etc., and esters solvent is as ethyl acetate etc., and alkali or sodium source can be sodium methylate, sodium hydroxide.
The present invention includes a kind of medicinal compositions, comprise crystallization Mycophenolate Sodium MK1 of the present invention, the MK2 and the MK3 that treat significant quantity, and at least one pharmaceutically acceptable carrier.
Pharmaceutically acceptable auxiliary material or carrier auxiliary material as conventional in oral preparations, injection auxiliary material etc., and be prepared to oral preparation as dosage forms such as enteric coated tablet, enteric coated capsule, particle, injection liquid, freeze-dried powders, auxiliary material, carrier and the preparation technique adopting is general known technology, in " pharmaceutics " (Higher Education Publishing House, the 4th edition) etc. have a detailed description in books, dosage form and specification of quality thereof are described and are as the criterion with existing Chinese Pharmacopoeia.
The preparation method of Mycophenolate Sodium crystal form M K1 of the present invention comprises the following steps: Mycophenolate Mofetil is dissolved in methanol solution, add equimolar sodium methylate, freezing crystallization, filters, and drying under reduced pressure obtains.
The preparation method of Mycophenolate Sodium crystal form M K2 of the present invention comprises the following steps: Mycophenolate Mofetil is dissolved in solution in ethyl acetate, add equimolar sodium methylate reaction, freezing crystallization, filters, and drying under reduced pressure obtains.
The preparation method of Mycophenolate Sodium crystal form M K3 of the present invention comprises the following steps: Mycophenolate Mofetil is dissolved in solution in ethyl acetate, add equimolar sodium hydroxide solution reaction, freezing crystallization, filters, and drying under reduced pressure obtains.
Embodiment
Following examples are just described more specifically the present invention, and the present invention is not limited in the content of following examples.
Embodiment 1
In the reaction flask of 500ml, add MMF 10.43g, add methyl alcohol 52ml, under room temperature, drip 30% methanol solution of sodium methylate 3.8ml, reflux, solid dissolves completely, freezing static crystallization, and a large amount of solids are separated out, filter, 50 ℃ of vacuum-dryings obtain off-white powder solid 4.4g for 12 hours, yield 64.27%, and its X-ray powder diffraction is shown in Fig. 1.
In the reaction flask of 500ml, add MMF 10.43g, add ethyl acetate 250ml, under room temperature, drip 30% methanol solution of sodium methylate 3.8ml, reflux, freezing static crystallization, a large amount of solids are separated out, and filter, and 50 ℃ of vacuum-dryings obtain off-white powder solid 1.2g for 12 hours, yield 17.53%, its X-ray powder diffraction is shown in Fig. 2.
In the reaction flask of 500ml, add MMF 10.43g, add ethyl acetate 200ml, under room temperature, drip the sodium hydroxide solution 5ml of 4N, reflux, freezing static crystallization, a large amount of solids are separated out, and filter, and 50 ℃ of vacuum-dryings obtain off-white powder solid 3.9g for 12 hours, yield 45.2%, its X-ray powder diffraction is shown in Fig. 3.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction characteristic pattern of Mycophenolate Sodium crystal form M K1.
Fig. 2 is the X-ray powder diffraction characteristic pattern of Mycophenolate Sodium crystal form M K2.
Fig. 3 is the X-ray powder diffraction characteristic pattern of Mycophenolate Sodium crystal form M K3.
Claims (3)
1. a crystallization Mycophenolate Sodium, is characterized in that having the powder X-ray RD collection of illustrative plates of accompanying drawing 1 containing 4.48,12.02,13.37,17.23 and 17.85 ± 0.2 degree 2-θ peaks.
2. the preparation method of the crystal formation of Mycophenolate Sodium as claimed in claim 1, is characterized in that: Mycophenolate Mofetil is dissolved in methanol solution, add equimolar sodium methylate, freezing crystallization, filters, and drying under reduced pressure obtains.
3. a medicinal compositions, is characterized in that: comprise the crystallization Mycophenolate Sodium as claimed in claim 1 for the treatment of significant quantity, and at least one pharmaceutically acceptable carrier.
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| CN201410153692.3A CN103880799A (en) | 2010-11-16 | 2010-11-16 | New crystal forms of sodium mycophenolate and preparation method thereof |
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| CN201410153692.3A CN103880799A (en) | 2010-11-16 | 2010-11-16 | New crystal forms of sodium mycophenolate and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1215991A (en) * | 1996-04-12 | 1999-05-05 | 诺瓦提斯公司 | Enteric-coated pharmaceutical compositions of mycophenolate |
| CN101052631A (en) * | 2004-07-20 | 2007-10-10 | 特瓦药厂私人有限公司 | Crystalline mycophenolate sodium |
| CN101333201A (en) * | 2003-01-20 | 2008-12-31 | 诺瓦提斯公司 | Crystal of needle-shaped medical substance and use thereof, medicine composite containing the crystal |
-
2010
- 2010-11-16 CN CN201410153692.3A patent/CN103880799A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1215991A (en) * | 1996-04-12 | 1999-05-05 | 诺瓦提斯公司 | Enteric-coated pharmaceutical compositions of mycophenolate |
| CN101333201A (en) * | 2003-01-20 | 2008-12-31 | 诺瓦提斯公司 | Crystal of needle-shaped medical substance and use thereof, medicine composite containing the crystal |
| CN101052631A (en) * | 2004-07-20 | 2007-10-10 | 特瓦药厂私人有限公司 | Crystalline mycophenolate sodium |
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Application publication date: 20140625 |