CN101781194A - Crystal form V of sofalcone and preparation method and application thereof - Google Patents

Crystal form V of sofalcone and preparation method and application thereof Download PDF

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CN101781194A
CN101781194A CN200910229072A CN200910229072A CN101781194A CN 101781194 A CN101781194 A CN 101781194A CN 200910229072 A CN200910229072 A CN 200910229072A CN 200910229072 A CN200910229072 A CN 200910229072A CN 101781194 A CN101781194 A CN 101781194A
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sofalcone
crystal form
preparation
mixed solution
thf
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CN101781194B (en
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刘颖
刘默
刘冰妮
刘登科
陈继方
吴疆
邹美香
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention relates to a crystal form V of sofalcone and a preparation method thereof, and a medicinal composition prepared from the crystal form V of the sofalcone obtained by the invention and application thereof. The crystal form V of the sofalcone is characterized by a powder X-ray diffraction pattern and an infrared spectrogram of the crystal form V of the sofalcone.

Description

Crystalline form V of sofalcone and its production and use
Technical field
The invention belongs to the pharmaceutical field of anti-gastric-ulcer, acute or chronic gastritis, more particularly, relate to [5-(3-methyl-2-butene base) oxygen base-2-[3-[4-(3-methyl-2-butene base) oxygen base] phenyl-1-oxo-2-propenyl of sofalcone (sofalcone) or formula (I)] phenoxy group] crystal form V and preparation method thereof of acetate, the pharmaceutical composition that contains it and the purposes in making anti-gastric-ulcer, acute or chronic gastritis medicine thereof.
Background technology
Sofalcone (sofalcone); chemistry [5-(3-methyl-2-butene base) oxygen base-2-[3-[4-(3-methyl-2-butene base) oxygen base] phenyl-1-oxo-2-propenyl by name] phenoxy group] acetate; be a kind of gastric mucosal protection agent and tissue repair agent; can be used for the treatment of stomach ulcer, acute or chronic gastritis; developed by the big positive drugmaker of Japan, go on the market in Japan in March, 1984.
Chemical structure:
Molecular formula: C 27H 30O 6
Molecular weight: 450.5
Sofalcone is a kind of effective gastric mucosa protectant; can increase stomach volume of blood flow, expansion stomach mucous membrane blood vessel, increase the stomach-tissue oxygen-consumption, promote the stomach mucous membrane reparation, increase the coat of the stomach constituent, increase prostaglandin(PG) content in the stomach-tissue, mainly bring into play its result of treatment by strengthening defense factor.Applying surplus clinical study and ten year shows that this medicine especially has curative effect preferably to stomach ulcer to peptide ulceration, also can be used for the treatment of diseases such as chronic gastritis, has curative effect height, the little characteristics of side effect.
The existing both at home and abroad report of the preparation method of this product, as document Chem.Pharm.Bull.1979,27 (12): 2943~2953 and document U.S.4085135, Chinese patent CN1733682A, the preparation method of sofalcone, the pharmaceutical composition that contains them and preparation treatment stomach ulcer have been put down in writing among the CN101434533A, the purposes of chronic gastritis medicine, but all do not relate to the crystal formation of sofalcone.
The poorly water-soluble of sofalcone is used in the oral preparations at present, and this compound that in view of the pharmacy value of this compound, obtain the purity height, has very definite crystal formation and a favorable reproducibility is important.
Summary of the invention
An object of the present invention is to provide the sofalcone crystal form V.
Another object of the present invention provides the preparation method of sofalcone crystal form V.
A further object of the invention provides the sofalcone crystal form V as effective constituent, and the medicinal compositions that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, and at anti-gastric-ulcer, the application of chronic gastritis medicine aspect.
Now content of the present invention is specifically described in conjunction with the object of the invention.
Sofalcone of the present invention has following structural formula:
Figure G2009102290722D00021
The sofalcone crystal form V has following feature:
Measure with D/Max-2500 type x-ray diffractometer, condition determination: CuKa, 40KV, 100mA, its collection of illustrative plates have following diffraction angle (2 θ), spacing (d value) and intensity (%), the error of 2 θ is 0.2.
The sofalcone crystal form V, with Potassium Bromide (KBr) compressing tablet, the infrared spectrogram that records has following charateristic avsorption band:
3472cm -1、2925cm -1、1770cm -1、1716cm -1、1453cm -1、1420cm -1、1245cm -1、949cm -1、746cm -1、693cm -1
Be used to prepare the sofalcone of sofalcone crystal form V, can conveniently make by two kinds of synthetic methods.A kind of is document Chem.Pharm.Bull.1979,27 (12): and reported method in 2943~2953, reaction scheme is as follows:
Figure G2009102290722D00032
Figure G2009102290722D00041
Also have synthetic route and method among the patent CN101434533A that a kind of inventor of being applies for, be expressed as follows with reaction formula:
Figure G2009102290722D00042
The synthetic sofalcone is refining with ethanol, and through proton nmr spectra ( 1H-NMR), carbon-13 nmr spectra ( 13C-NMR) prove conclusively its chemical structure (seeing accompanying drawing 1,2).Testing tool is Bruker AV 400 type nuclear magnetic resonance analyser, and deuterated reagent is the DMSO-d6 of Cambridge Isotope Laboratories company.The maximum single impurity that high performance liquid chromatography (HPLC) records is 0.235%.
But above-mentioned product promptly uses single solvent ethanol to re-refine twice, and maximum single impurity still is not less than 0.2%.
The crystal form V of sofalcone is that crystallization obtains in the mixed solution of ethanol-tetrahydrofuran (THF).The usage quantity of mixed solution be 3~12 times of the sofalcone quality (volume-mass ratio, mL/g), wherein preferred 5~10 times.
Tetrahydrofuran (THF) accounts for 10~50% of mixed solution cumulative volume, and wherein preferred 20~40%.
Temperature during dissolving is 50 ℃~73 ℃.Naturally be cooled to room temperature then, placed 1~5 hour, promptly obtain the new crystal V-type of sofalcone.
Specific operation process is:
Get a certain amount of sofalcone, add ethanol one tetrahydrofuran (THF) mixed solution, heated and stirred after the dissolving, naturally cools to room temperature, is incubated for some time again.Separate out solid, filter, promptly get the sofalcone crystal form V.
Then through the X-powder diffraction method, maximum infrared absorption spectrometry feature.
Do not contain crystal water and recrystallisation solvent in the thermogravimetric analysis demonstration sofalcone crystal form V.
The crystal form V purity height that this method makes, single impurity have reached the relevant requirements of U.S. food Drug Administration (FDA) less than 1 ‰ (seeing accompanying drawing 3), and be very important to making high-quality medicine.In the described process parameters range of this method, repeat a plurality of batches, circulation ratio is fabulous.
Sofalcone crystal form V preparation of pharmaceutical compositions of the present invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, usually, the weight range of active compound is 0.5%~90% (weight) of composition.Another preferred range is 0.5%-70%.
Figure of description
Fig. 1 be the sofalcone proton nmr spectra ( 1H-NMR).
Fig. 2 be the sofalcone carbon-13 nmr spectra ( 13C-NMR).
Fig. 3 is the HPLC spectrogram of sofalcone crystal form V.
Fig. 4 is the X-powder diagram of sofalcone crystal form V.
Fig. 5 is the infrared spectrogram of sofalcone crystal form V.
Embodiment:
Below in conjunction with embodiment the present invention is described further, embodiment only is indicative, means that never it limits the scope of the invention by any way.
Embodiment 1
Take by weighing sofalcone 20.0g, add 60mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 1: 1), be heated to 50 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 5 hours.Separate out solid, filter, (vacuum tightness 0.07mPa~0.08mPa) about 24 hours gets yellow crystalline powder in vacuum-drying.
Embodiment 2
Take by weighing sofalcone 20.0g, add 160mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 7: 3), be heated to 65 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 3 hours.Separate out solid, filter, (vacuum tightness 0.07mPa~0.08mPa) about 24 hours gets yellow crystalline powder in vacuum-drying.
Embodiment 3
Take by weighing sofalcone 20.0g, add 240mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 9: 1), be heated to 73 ℃, after the stirring and dissolving, filtered while hot, filtrate naturally cools to room temperature, places 1 hour.Separate out solid, filter, (vacuum tightness 0.07mPa~0.08mPa) about 24 hours gets yellow crystalline powder in vacuum-drying.
Embodiment 4
Every tablet preparation that contains the 100mg activeconstituents:
Consumption/sheet
Sofalcone crystal form V 100mg
Lactose 80mg
Microcrystalline Cellulose 20mg
Starch 50mg
Hypromellose 10mg
Add 5mg in the carboxymethylstach sodium and add 5mg
Magnesium Stearate 1mg
Technology: activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves respectively, take by weighing and abundant mixing by recipe quantity, the 2% hydroxyl methylcellulose aqueous solution joined in the said mixture granulate, cross 20 mesh sieve system softwoods, make wet granular in 45~55 ℃ dry about 2-3 hour, with remain carboxymethylstach sodium, Magnesium Stearate joins compressing tablet in the above-mentioned dried particles.
Embodiment 5
Every capsule contains the capsule preparation of 80mg activeconstituents:
Consumption/capsule
Sofalcone crystal form V 80mg
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium starch glycolate 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate 1mg
Talcum powder 1mg
Technology: activeconstituents, auxiliary material are crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, Magnesium Stearate and talcum powder and particle are mixed whole; measure intermediate content, with No. 2 capsule cans.

Claims (9)

1. the crystal form V of a sofalcone (sofalcone), its powder x-ray diffraction collection of illustrative plates has following diffraction angle (2 θ angle), spacing (d value) and relative intensity.Described 2 θ angular units are degree, and error is 0.2.
Figure F2009102290722C00011
2. according to the crystal form V of the sofalcone (sofalcone) of claim 1, the characteristic absorbance that its infrared spectra shows is as follows:
3472cm -1、2925cm -1、1770cm -1、1716cm -1、1453cm -1、1420cm -1、1245cm -1、949cm -1、746cm -1、693cm -1
3. the preparation method of a sofalcone (sofalcone) crystal form V is characterized in that: after sofalcone is dissolved, naturally cool to room temperature in warm ethanol-tetrahydrofuran (THF) mixed solution, be incubated for some time again, separate out crystal.
4. the preparation method of a sofalcone crystal form V as claimed in claim 3, described warm ethanol-tetrahydrofuran (THF) mixed solution, the cumulative volume of mixed solution are 3~12 times (mL/g) of corresponding sofalcone quality.
5. the preparation method of a sofalcone crystal form V as claimed in claim 3, described ethanol-tetrahydrofuran (THF) mixed solution, the tetrahydrofuran (THF) volume accounts for 10%~50% of mixed solution cumulative volume, and wherein preferred 20~40%.
6. the preparation method of a sofalcone crystal form V as claimed in claim 3, described warm ethanol-tetrahydrofuran (THF) mixed solution, temperature is 50 ℃~73 ℃.
7. the preparation method of a sofalcone crystal form V as claimed in claim 3, described insulation for some time is 1~5 hour, wherein preferred 2~3 hours.
8. pharmaceutical composition is characterized in that: comprise as activeconstituents as the described sofalcone crystal form V of claim 1~2 and one or more pharmaceutically useful inert non-toxic carriers.
9. be coated with as the usefulness of the described sofalcone crystal form V of claim 1~2 in making anti-gastric-ulcer, chronic gastritis medicine.
CN 200910229072 2009-12-10 2009-12-10 Crystal form V of sofalcone and preparation method and application thereof Expired - Fee Related CN101781194B (en)

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5297950A (en) * 1976-02-13 1977-08-17 Taisho Pharmaceut Co Ltd Chalconeether derivatives
US5811547A (en) * 1992-10-14 1998-09-22 Nippon Shinyaju Co., Ltd. Method for inducing crystalline state transition in medicinal substance
CN1733682A (en) * 2005-08-08 2006-02-15 阮华君 Sofalcone preparation method

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