CN101781194B - Crystal form V of sofalcone and preparation method and application thereof - Google Patents

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 acetic acid, 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] acetic acid; a kind of gastric mucosa protective agent and tissue repair agent; can be used for the treatment of stomach ulcer, acute or chronic gastritis; developed by the large 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 in stomach-tissue, mainly bring into play its result for the treatment of by strengthening defense factor.Show through applying of clinical study and more than ten years, this medicine especially has curative effect preferably to stomach ulcer to peptide ulceration, also can be used for the treatment of the diseases such as chronic gastritis, has the advantages that curative effect is high, side effect is little.

The preparation method of this product has been reported both at home and abroad, 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 in 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 oral preparations at present, and in view of the pharmacy value of this compound, acquisition purity is high, this compound that have very definite crystal formation and 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 is to provide the preparation method of sofalcone crystal form V.

A further object of the invention is to provide 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 in conjunction with the object of the invention, content of the present invention is specifically described.

Sofalcone of the present invention has following structural formula:

The sofalcone crystal form V has following characteristics:

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。

For the preparation of the sofalcone of sofalcone crystal form V, can conveniently be made by two kinds of synthetic methods.A kind of is document Chem.Pharm.Bull.1979,27 (12): and the method for report in 2943～2953, reaction scheme is as follows:

Also have synthetic route and method in the patent CN101434533A that a kind of inventor of being applies for, be expressed as follows with reaction formula:

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 contaminant that high performance liquid chromatography (HPLC) records is 0.235%.

But above-mentioned product namely uses single solvent ethanol to re-refine twice, and maximum single contaminant 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 ℃.Then naturally be cooled to room temperature, placed 1～5 hour, namely 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 dissolving, naturally cools to room temperature, then is incubated for some time.Separate out solid, filter, namely 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 thermogravimetric analysis demonstration sofalcone crystal form V.

The crystal form V purity that the method makes is high, and single contaminant has reached the relevant requirements of U.S. food Drug Administration (FDA) less than 1 ‰ (seeing accompanying drawing 3), and is very important to making high-quality medicine.In the described process parameters range of the method, repeat a plurality of batches, circulation ratio is fabulous.

Sofalcone crystal form V pharmaceutical composition of the present invention is prepared as follows: Application standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle and be combined and be prepared into particulate or microballoon.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet etc.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 such as 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 etc.

The amount of the active ingredient that contains in pharmaceutical composition and unit dosage form can specifically be applied according to patient's the state of an illness, the situation of diagnosis, the amount of compound used or concentration are regulated in a wider scope, usually, the weight range of active compound is 0.5%～90% (weight) of composition.Another preferred scope 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 is only indicative, means that never it limits the scope of the invention by any way.

Embodiment 1

Take sofalcone 20.0g, add 60mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 1: 1), be heated to 50 ℃, after 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) approximately 24 hours gets yellow crystalline powder in vacuum-drying.

Embodiment 2

Take sofalcone 20.0g, add 160mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 7: 3), be heated to 65 ℃, after 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) approximately 24 hours gets yellow crystalline powder in vacuum-drying.

Embodiment 3

Take sofalcone 20.0g, add 240mL ethanol-tetrahydrofuran (THF) mixed solution (volume ratio 9: 1), be heated to 73 ℃, after 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) approximately 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 carboxymethylstach sodium and add 5mg

Magnesium Stearate 1mg

Technique: activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed respectively 100 mesh sieves, take and abundant mixing by recipe quantity, the 2% hydroxyl methylcellulose aqueous solution is joined in said mixture granulate, cross 20 mesh sieve softwoods processed, make wet granular in 45～55 ℃ of dryings approximately 2-3 hour, residue carboxymethylstach sodium, Magnesium Stearate are joined compressing tablet in 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

Technique: activeconstituents, auxiliary material are crossed respectively 100 mesh sieves; the main ingredient and the auxiliary material that take recipe quantity fully mix; add hypromellose solution softwood processed in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry approximately 2-3 hour, Magnesium Stearate and talcum powder and particle are mixed whole grain; measure intermediate content, with No. 2 capsule cans.

Claims (8)

1. the crystal form V of a sofalcone (sofalcone), its powder x-ray diffraction collection of illustrative plates is as shown in Figure of description 4.

2. according to claim 1 the crystal form V of sofalcone (sofalcone), 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 crystal form V as claimed in claim 1 is characterized in that: sofalcone after dissolving, is naturally cooled to room temperature, then is incubated for some time, crystallize out in the ethanol of 50 ℃～73 ℃-tetrahydrofuran (THF) mixed solution.

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 20～40% of mixed solution cumulative volume.

6. the preparation method of a sofalcone crystal form V as claimed in claim 3, described insulation for some time is 2～3 hours.

7. a pharmaceutical composition, is characterized in that: comprise sofalcone crystal form V as claimed in claim 1 or 2 and one or more pharmaceutically useful inert non-toxic carriers as activeconstituents.

8. the purposes of sofalcone crystal form V as claimed in claim 1 or 2 in making anti-gastric-ulcer, chronic gastritis medicine.

Images