CN101781193B - Crystal form IV of sofalcone and preparation method and application thereof - Google Patents
Crystal form IV of sofalcone and preparation method and application thereof Download PDFInfo
- Publication number
- CN101781193B CN101781193B CN 200910229071 CN200910229071A CN101781193B CN 101781193 B CN101781193 B CN 101781193B CN 200910229071 CN200910229071 CN 200910229071 CN 200910229071 A CN200910229071 A CN 200910229071A CN 101781193 B CN101781193 B CN 101781193B
- Authority
- CN
- China
- Prior art keywords
- sofalcone
- preparation
- stirring reaction
- crystal form
- sodium hydroxide
- 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
- GFWRVVCDTLRWPK-KPKJPENVSA-N sofalcone Chemical compound C1=CC(OCC=C(C)C)=CC=C1\C=C\C(=O)C1=CC=C(OCC=C(C)C)C=C1OCC(O)=O GFWRVVCDTLRWPK-KPKJPENVSA-N 0.000 title claims abstract description 53
- 229950004782 sofalcone Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000013078 crystal Substances 0.000 title abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 14
- 208000007882 Gastritis Diseases 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 7
- 208000023652 chronic gastritis Diseases 0.000 claims description 7
- 201000005917 gastric ulcer Diseases 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 238000002835 absorbance Methods 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 238000002329 infrared spectrum Methods 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 5
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 239000008108 microcrystalline cellulose Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N trimethyl-ethylene Natural products CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- -1 phenyl-1-oxo-2-propenyl Chemical group 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011122 softwood Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 240000006474 Theobroma bicolor Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 229910000400 magnesium phosphate tribasic Inorganic materials 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crystal form IV of sofalcone and a preparation method thereof, and a medicinal composition prepared from the crystal form IV of the sofalcone obtained by the invention and application thereof. The crystal form IV of the sofalcone is characterized by a powder X-ray diffraction pattern and an infrared spectrogram of the crystal form IV of the sofalcone.
Description
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] form IV 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 form IV.
Another object of the present invention is to provide the preparation method of sofalcone form IV.
A further object of the invention is to provide the sofalcone form IV 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 form IV 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 form IV, with Potassium Bromide (KBr) compressing tablet, the infrared spectrogram that records has following charateristic avsorption band:
3565cm
-1、3391cm
-1、2934cm
-1、2592cm
-1、1782cm
-1、1720cm
-1、1444cm
-1、1251cm
-1、1091cm
-1、834cm
-1。
For the preparation of the sofalcone of sofalcone form IV, 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 form IV of sofalcone is that the method by the soda acid salify obtains.Use methylene dichloride, trichloromethane, ethyl acetate, toluene etc. and the immiscible organic solvent preparation of water.The organic solvent usage quantity be 5～30 times of the sofalcone quality (volume-mass ratio, mL/g).
The concentration of sodium hydroxide and the potassium hydroxide aqueous solution saturated solution concentration (sodium hydroxide is about 40%, and potassium hydroxide is about 30%) that is 10% (w/w) to the normal temperature wherein.
Temperature during stirring reaction is-20 ℃～35 ℃, and wherein preferred-10 ℃～5 ℃, the time is 0.5～2.5 hour.
Specific operation process is:
Sofalcone is dissolved in organic solvent, the aqueous solution that adds sodium hydroxide or potassium hydroxide to pH be 10, the vigorous stirring reaction reacts complete rear standing, separatory, divide the water intaking layer, slowly drip concentrated hydrochloric acid under ice-water bath and regulate pH to 1～2, separate out solid, filter, vacuum-drying gets yellow powder shape sofalcone form IV.
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 form IV.
The form IV 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 form IV 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 form IV.
Fig. 4 is the X-powder diagram of sofalcone form IV.
Fig. 5 is the infrared spectrogram of sofalcone form IV.
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.
Take sofalcone 4.0g, add the 20mL methylene dichloride that it is dissolved, cryosel is bathed and is cooled to-15 ℃, and under vigorous stirring, splashing into 15% aqueous sodium hydroxide solution is 10 to pH, continuation stirring reaction 2.5 hours.React and stop after complete stirring, standing separatory, minute water intaking layer slowly drips concentrated hydrochloric acid and regulates pH to 1～2 under ice-water bath, separate out solid, filters, and (vacuum tightness 0.07mPa～0.08mPa) approximately 24 hours gets yellow crystalline powder in filter cake vacuum-drying.
Take sofalcone 4.0g, add the 60mL ethyl acetate that it is dissolved, ice-water bath is cooled to 5 ℃, and under vigorous stirring, splashing into 40% aqueous sodium hydroxide solution is 10 to pH, continuation stirring reaction 1.5 hours.React and stop after complete stirring, standing separatory, minute water intaking layer slowly drips concentrated hydrochloric acid and regulates pH to 1～2 under ice-water bath, separate out solid, filters, and (vacuum tightness 0.07mPa～0.08mPa) approximately 24 hours gets yellow crystalline powder in filter cake vacuum-drying.
Take sofalcone 4.0g, add 120mL toluene that it is dissolved, vigorous stirring under room temperature, splashing into 30% potassium hydroxide aqueous solution is 10 to pH, continuation stirring reaction 0.5 hour.React and stop after complete stirring, standing separatory, minute water intaking layer slowly drips concentrated hydrochloric acid and regulates pH to 1～2 under ice-water bath, separate out solid, filters, and (vacuum tightness 0.07mPa～0.08mPa) approximately 24 hours gets yellow crystalline powder in filter cake vacuum-drying.
Every tablet preparation that contains the 100mg activeconstituents:
Consumption/sheet
Sofalcone form IV 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.
Every capsule contains the capsule preparation of 80mg activeconstituents:
Consumption/capsule
Sofalcone form IV 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 (9)
1. the form IV 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 form IV of sofalcone (sofalcone), the characteristic absorbance that its infrared spectra shows is as follows:
3565cm
-1、3391cm
-1、2934cm
-1、2592cm
-1、1782cm
-1、1720cm
-1、1444cm
-1、1251cm
-1、1091cm
-1、834cm
-1。
3. the preparation method of a sofalcone form IV as claimed in claim 1, it is characterized in that: sofalcone is dissolved in methylene dichloride, ethyl acetate or toluene, the aqueous solution that adds sodium hydroxide or potassium hydroxide to pH be 10, the vigorous stirring reaction, standing, minute water intaking layer, regulate pH to 1～2 with concentrated hydrochloric acid, separate out solid, filter, get yellow powder shape sofalcone form IV.
4. the preparation method of a sofalcone form IV as claimed in claim 3, the volume of described organic solvent is 5～30 times (mL/g) of corresponding sofalcone quality.
5. the preparation method of a sofalcone form IV as claimed in claim 3, the concentration of described aqueous sodium hydroxide solution is 10%～40% (w/w), the concentration of potassium hydroxide aqueous solution is 10%～30% (w/w).
6. the preparation method of a sofalcone form IV as claimed in claim 3, the temperature during described stirring reaction is-10 ℃～5 ℃.
7. the preparation method of a sofalcone form IV as claimed in claim 3, the time of described stirring reaction is 0.5～2.5 hour.
8. a pharmaceutical composition, is characterized in that: comprise sofalcone form IV as claimed in claim 1 or 2 and one or more pharmaceutically useful inert non-toxic carriers as activeconstituents.
9. the purposes of sofalcone form IV as claimed in claim 1 or 2 in making anti-gastric-ulcer, chronic gastritis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910229071 CN101781193B (en) | 2009-12-10 | 2009-12-10 | Crystal form IV of sofalcone and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910229071 CN101781193B (en) | 2009-12-10 | 2009-12-10 | Crystal form IV of sofalcone and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101781193A CN101781193A (en) | 2010-07-21 |
| CN101781193B true CN101781193B (en) | 2013-05-15 |
Family
ID=42521359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910229071 Expired - Fee Related CN101781193B (en) | 2009-12-10 | 2009-12-10 | Crystal form IV of sofalcone and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101781193B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4085135A (en) * | 1976-02-13 | 1978-04-18 | Taisho Pharmaceutical Co., Ltd. | 2-(Carboxymethoxy)-chalcones |
| 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 |
-
2009
- 2009-12-10 CN CN 200910229071 patent/CN101781193B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4085135A (en) * | 1976-02-13 | 1978-04-18 | Taisho Pharmaceutical Co., Ltd. | 2-(Carboxymethoxy)-chalcones |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101781193A (en) | 2010-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106349192B (en) | The eutectic of orlistat and amino acid and include eutectiferous pharmaceutical composition | |
| CN104447771A (en) | Stable asenapine maleate sublingual compound | |
| CN104045615B (en) | (1S) crystal form A and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose | |
| CN101684108B (en) | 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and composition thereof | |
| CN101781193B (en) | Crystal form IV of sofalcone and preparation method and application thereof | |
| CN101735039B (en) | Crystal form II of sofalcone and preparation method and application thereof | |
| CN101781194B (en) | Crystal form V of sofalcone and preparation method and application thereof | |
| CN101735040B (en) | Crystal form III of sofalcone and preparation method and application thereof | |
| CN101781192B (en) | Crystal form VI of sofalcone and preparation method and application thereof | |
| CN101792385B (en) | Sofalcone crystals VIII, preparation method thereof and use thereof | |
| CN101817742B (en) | Crystal form X of sofalcone, preparation method and use thereof | |
| CN101735038B (en) | Crystal form I of sofalcone and preparation method and application thereof | |
| CN101817741B (en) | Crystal form IX of sofalcone, preparation method and use thereof | |
| CN101781195B (en) | Crystal form VII of sofalcone and preparation method and application thereof | |
| CN104829467A (en) | Ambroxol hydrochloride dihydrate compound | |
| CN112409246A (en) | Novel pirfenidone crystal form and preparation method thereof | |
| CN104140429B (en) | Lixivaptan crystalline form V and its production and use | |
| CN104693192A (en) | Crystal form A of compound as well as preparation method and application thereof | |
| CN103724359B (en) | A kind of amorphous cefotetan acid and prepared the method for Cefotetan Disodium and containing the pharmaceutical composition of this Cefotetan Disodium by it | |
| CN104045614B (en) | (1S) crystal C and its preparation method and application of-1-[the chloro-3-of 4-(4-ethoxy benzyl) phenyl]-1,6-dideoxy-D-Glucose | |
| CN104059070B (en) | Lixivaptan crystalline form I and its production and use | |
| CN107663198A (en) | Olmesartan medoxomil and its production and use | |
| CN101735204B (en) | Crystalline form III of azimilide dihydrochloride, preparation method and application thereof | |
| CN101735203B (en) | Azimilide dihydrochloride crystal form II as well as preparation method and application thereof | |
| CN104370810B (en) | Montelukast sodium compound |
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 | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 300193 Anshan West Road, Nankai District, Nankai District, Tianjin Patentee after: Tianjin Institute of Pharmaceutical Research Co.,Ltd. Address before: 300193 Anshan West Road, Nankai District, Nankai District, Tianjin Patentee before: Tianjin Institute of Pharmaceutical Research |
|
| DD01 | Delivery of document by public notice |
Addressee: Wu Jiang Document name: payment instructions |
|
| DD01 | Delivery of document by public notice | ||
| DD01 | Delivery of document by public notice |
Addressee: Wu Jiang Document name: Notice of patent termination |
|
| DD01 | Delivery of document by public notice | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130515 Termination date: 20211210 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |