CN105153021A - Crystal form of pyritinol maleate and preparation method thereof - Google Patents
Crystal form of pyritinol maleate and preparation method thereof Download PDFInfo
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- CN105153021A CN105153021A CN201410260932.XA CN201410260932A CN105153021A CN 105153021 A CN105153021 A CN 105153021A CN 201410260932 A CN201410260932 A CN 201410260932A CN 105153021 A CN105153021 A CN 105153021A
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- Prior art keywords
- pyritinol
- toxilic acid
- crystal form
- crystal
- ray powder
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- SIXLXDIJGIWWFU-UHFFFAOYSA-N pyritinol Chemical compound OCC1=C(O)C(C)=NC=C1CSSCC1=CN=C(C)C(O)=C1CO SIXLXDIJGIWWFU-UHFFFAOYSA-N 0.000 title claims abstract description 60
- 229960004986 pyritinol Drugs 0.000 title claims abstract description 55
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 49
- 239000013078 crystal Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title abstract description 7
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 7
- 239000007924 injection Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 claims description 3
- 206010057315 Daydreaming Diseases 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 201000009906 Meningitis Diseases 0.000 claims description 3
- 206010039966 Senile dementia Diseases 0.000 claims description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 3
- 210000004556 brain Anatomy 0.000 claims description 3
- 208000002173 dizziness Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000002996 emotional effect Effects 0.000 claims description 3
- 206010014599 encephalitis Diseases 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 206010022437 insomnia Diseases 0.000 claims description 3
- 201000005851 intracranial arteriosclerosis Diseases 0.000 claims description 3
- 230000003340 mental effect Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 230000004060 metabolic process Effects 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 2
- AMQJAKKATFMFTR-UHFFFAOYSA-N 2,6-dimethylpyridin-3-ol Chemical compound CC1=CC=C(O)C(C)=N1 AMQJAKKATFMFTR-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 abstract 1
- 230000007774 longterm Effects 0.000 abstract 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 4
- VFEKMAOUJHONFD-UHFFFAOYSA-N 5-[[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methyldisulfanyl]methyl]-4-(hydroxymethyl)-2-methylpyridin-3-ol;hydrate;dihydrochloride Chemical compound O.Cl.Cl.OCC1=C(O)C(C)=NC=C1CSSCC1=CN=C(C)C(O)=C1CO VFEKMAOUJHONFD-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OXUMVEOKAMNGER-UHFFFAOYSA-N C.OC=1C=CC=NC1C Chemical compound C.OC=1C=CC=NC1C OXUMVEOKAMNGER-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 230000037354 amino acid metabolism Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 231100000652 hormesis Toxicity 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel crystal form of 3,3-(dithiobis methylene)bis(5-hydroxy-6-methyl-pyridyl methane) dimaleic acid, namely pyritinol maleate, and a preparation method thereof, wherein the novel crystal form is A form of pyritinol maleate. The A form of pyritinol maleate has stable physical and chemical properties, and is suitable for long-term storage and applies to preparation.
Description
Technical field
The present invention relates to new crystal of toxilic acid pyritinol (i.e. 3,3-(dithio methylene radical) two (5-hydroxyl-6-methvl-pyridinium methane) two maleic acids) and preparation method thereof, and pharmaceutical composition and medicinal use.Belong to medical art
Background technology
Pyritinol nowadays main application form is the hydrochloride of pyritinol, and also known as pyritionol hydrochloride neuroxin, Pyrithioxine hydrochloride can promote glucose and amino acid metabolism in brain, improve whole body assimilation, increase Flow of carotid artery, cerebral function improvement, edge system and reticulated structure also have hormesis.Clinical application is in the dizzy distending pain of cerebral trauma sequela, encephalitis and meningitis sequela etc., insomnia, hypomnesis, absent minded, emotional change; Also for cerebral arteriosclerosis, senile dementia mental symptom.Pyritinol hydrochloride in the market, there are oral and injection two kinds of route of administration, due to Pyrithioxine hydrochloride aqueous solution slant acidity, during this medicine of intravenous drip, the discomfort such as injection site pain, swollen blood vessels easily occur, and oral preparations bioavailability is poor, realizing still unrecovered patient cannot use.More side effect causes the clinical application of Pyrithioxine hydrochloride to be greatly restricted.
In order to solve injection of pyritinol hydrochloride existing issue, the inorganic acid radical of Pyrithioxine hydrochloride being changed to organic acid is a kind of feasible thinking, discloses the method for making of organic salt of pyritinol in patent CN200710026886.7, wherein preferred pyritinol nicotinate.
The present inventor is in the process of research toxilic acid pyritinol, also unexpectedly obtain a kind of new crystal of toxilic acid pyritinol, and in prior art, do not have the research of toxilic acid pyritinol crystal formation to report yet, this crystal formation has obvious X-ray powder diffraction feature, and preparation method is simple, chemical stability is excellent.Toxilic acid pyritinol new crystal of the present invention, the pharmaceutical salts that pyritinol is new---a kind of crystal formation of toxilic acid pyritinol, the new pharmaceutical salts toxilic acid pyritinol of pyritinol (or claiming pyritinol maleate) is see the application for a patent for invention of Chinese Patent Application No. 201410251076.1, and the application introduces the full content of the application for a patent for invention of Chinese Patent Application No. 201410251076.1.
Summary of the invention
The object of the present invention is to provide a kind of new crystal of toxilic acid pyritinol, this crystal formation preparation method is simple, and chemical stability is excellent.
New crystal of the present invention, is defined as toxilic acid pyritinol crystal form A, it is characterized in that: its X-ray powder diffraction is about the position of 7.1 °, 14.3 °, 17.4 °, 21.5 °, 23.3 °, 27.6 ° to having characteristic diffraction peak in 2 θ values.Toxilic acid pyritinol structure is as shown in the formula shown in (I):
Above-mentioned new crystal of the present invention, it is included in 2 θ values further and is about the position of 7.1 °, 8.7 °, 10.8 °, 11.7 °, 14.3 °, 16.1 °, 17.2 °, 17.4 °, 18.7 °, 19.5 °, 20.1 °, 21.5 °, 22.0 °, 22.5 °, 23.3 °, 24.6 °, 25.1 °, 26.3 °, 27.6 °, 29.0 °, 30.3 °, 31.2 °, 32.2 °, 32.6 °, 34.0 °, 35.1 °, 36.2 °, 38.0 °, 38.5 ° to having characteristic diffraction peak.
More preferably, the toxilic acid pyritinol crystal form A that the present invention is described above, it has the X-ray powder diffraction pattern as Figure of description 1.
Toxilic acid pyritinol of the present invention, preferably the mass content of its crystal form A is generally greater than 75%, preferably greater than or equal to 85%, more preferably greater than or equal 95%.
The X-ray powder diffraction analysis of toxilic acid pyritinol crystal form A of the present invention is under envrionment temperature and ambient moisture, through Rigaku motor RIGAKUD/MAX2550/PC type polycrystalline X diffractometer CuK α source (
) measured." envrionment temperature " is generally 0 ~ 40 DEG C, and " ambient moisture " is generally the relative humidity of 30% ~ 80%.
The representational X-ray powder diffraction of toxilic acid pyritinol crystal form A of the present invention is listed in accompanying drawing 1." representational X-ray powder diffraction " refers to that the X-ray powder diffraction feature of this crystal formation meets the overall pattern of this collection of illustrative plates display, be understandable that, in test process, due to be subject to many factors (as test sample granularity, test time sample treatment process, instrument, test parameter, test operation etc.) impact, the X-ray powder diffraction measured by same crystal formation go out peak position or peak intensity has certain difference.In X-ray powder diffraction the experimental error of diffraction peak 2 θ value can be ± 0.2 °.
Present invention also offers a kind of preparation method of toxilic acid pyritinol crystal form A described above.In a specific embodiment, the preparation method of toxilic acid pyritinol crystal form A comprises the steps:
1) be dissolved in suitable solvent by toxilic acid, be warming up to certain temperature and make it clearly molten, obtain the solution of toxilic acid, wherein temperature is 0 ~ 100 DEG C, preferably 30 ~ 60 DEG C;
2) add pyritinol in the maleic acid solution upwards walked, stir clearly molten, after reaction terminates, cool and make it crystallization, recrystallization temperature is 0 ~ 70 DEG C, preferably 5 ~ 30 DEG C;
3) crystal of precipitation is carried out filtering or centrifugation;
4) will be separated the crystal that obtains dry, drying temperature is generally 30 ~ 100 DEG C, preferably 30 ~ 60 DEG C, can constant pressure and dry, also can drying under reduced pressure, and during drying under reduced pressure, vacuum tightness is generally 300 ~ 760mmHg, preferably 600 ~ 760mmHg.
In the method for above-mentioned embodiment, step 1) described in solvent comprise the mixture of one or more in acetone, ethanol, Virahol, DMF (DMF), water; Step 2) in the molar feed ratio of toxilic acid and pyritinol be 2 ~ 4:1, preferably 2 ~ 3.5:1.
In the method for above-mentioned embodiment, can be static during crystallization, also can be stir.
For investigating the stability of toxilic acid pyritinol crystal form A described above, carried out influence factor test, test-results is as following table:
| Test conditions | Whether content changes | Whether crystal formation changes |
| Place 30 days at temperature 30 DEG C ± 2 DEG C | Without considerable change | Do not change |
| Place 90 days at temperature 30 DEG C ± 2 DEG C | Without considerable change | Do not change |
| Place 30 days at temperature 60 C ± 2 DEG C | Without considerable change | Do not change |
| Place 90 days at temperature 60 C ± 2 DEG C | Without considerable change | Do not change |
Above-mentioned test-results shows, toxilic acid pyritinol crystal form A provided by the invention has stable physicochemical property, is suitable for long storage periods and is applied to preparation.
Toxilic acid pyritinol crystal form A of the present invention, it is the same with toxilic acid pyritinol, as the pharmaceutical salts of pyritinol, there is drug activity that pyritinol has, such as improving brain metabolism etc., be particularly applied to the improvement of the dizzy distending pain of cerebral trauma sequela, encephalitis or meningitis sequela etc., insomnia, hypomnesis, absent minded, emotional change; Or for cerebral arteriosclerosis, senile dementia mental symptom etc.The present inventor also finds, toxilic acid pyritinol crystal form A has good dissolution rate and solubleness, is not only convenient to preparation and the suitability for industrialized production of injection, and can makes oral preparations, have good bioavailability.Pharmacological experiment proves, injection liquid prepared by toxilic acid pyritinol crystal form A does not have blood vessel irritation, effectively solves the existing issue that Pyrithioxine hydrochloride exists.
The present invention also provides a kind of pharmaceutical composition, comprises the pyritinol toxilic acid crystal form A described above and pharmaceutically acceptable thinner and/or carrier for the treatment of significant quantity, such as oral preparations or injection.Pharmaceutical composition of the present invention only can also contain the compounds of this invention of effective dose.The effective dosage ranges of pyritinol maleate crystal form A of the present invention is that 0.04 ~ 0.5g is (with C
16h
20n
2o
4s
2meter), as made oral preparations, its unitary dose can be 0.04 ~ 0.4g, if 0.08g, 0.16g are (with C
16h
20n
2o
4s
2meter), as made injection, its unitary dose can be 0.04 ~ 0.4g, if 0.083g, 0.166g, 0.332g are (with C
16h
20n
2o
4s
2meter).
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern of toxilic acid pyritinol crystal form A.
Embodiment
The preparation of toxilic acid pyritinol crystal form A
Embodiment 1
Toxilic acid 3.8g is dissolved in 100ml ethanol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1 hour, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid toxilic acid pyritinol crystal form A 4.9g.X-ray powder diffraction analysis, as Fig. 1, its 2 θ value is as following table.
Embodiment 2
Toxilic acid 3.8g is dissolved in 100ml acetone, be warming up to 45 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 1.5 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.2g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
Embodiment 3
Toxilic acid 3.8g is dissolved in and adds 100ml Virahol, be warming up to 60 DEG C clearly molten, add pyritinol 5.0g, stir clearly molten, react 2 hours, cooling crystallization, filter, solid is drying under reduced pressure at 50 DEG C, obtains white crystalline solid 5.1g.It is toxilic acid pyritinol crystal form A that dry product does X-ray powder diffraction.
Claims (10)
1. a crystal form A for the toxilic acid pyritinol of following formula (I), is characterized in that: its X-ray powder diffraction is about the position of 7.1 °, 14.3 °, 17.4 °, 21.5 °, 23.3 °, 27.6 ° to having characteristic diffraction peak in 2 θ values,
。
2. toxilic acid pyritinol crystal form A as claimed in claim 1, is characterized in that: its X-ray powder diffraction is about the position of 7.1 °, 8.7 °, 10.8 °, 11.7 °, 14.3 °, 16.1 °, 17.2 °, 17.4 °, 18.7 °, 19.5 °, 20.1 °, 21.5 °, 22.0 °, 22.5 °, 23.3 °, 24.6 °, 25.1 °, 26.3 °, 27.6 °, 29.0 °, 30.3 °, 31.2 °, 32.2 °, 32.6 °, 34.0 °, 35.1 °, 36.2 °, 38.0 °, 38.5 ° to having characteristic diffraction peak in 2 θ values.
3. toxilic acid pyritinol crystal form A as claimed in claim 1 or 2, is characterized in that it has the X-ray powder diffraction pattern as Figure of description 1.
4. prepare a method for the toxilic acid pyritinol crystal form A as described in claim 1-3, comprise the steps:
1) toxilic acid is dissolved in suitable solvent, is warming up to 30 ~ 60 DEG C and makes it clearly molten;
2) adding pyritinol stirs clearly molten, and cooling makes it crystallization;
3) crystal of precipitation is carried out filtering or centrifugation;
4) dry by being separated the crystal obtained.
5. method as claimed in claim 4, is characterized in that step 1) described in solvent selected from acetone, ethanol, Virahol, DMF (DMF), the mixture of one or more in water.
6. method as claimed in claim 4, is characterized in that step 2) in the molar feed ratio of toxilic acid and pyritinol be 2 ~ 4:1.
7. a pharmaceutical composition, comprises the toxilic acid pyritinol crystal form A according to claim 1 for the treatment of significant quantity and pharmaceutically acceptable diluent or carrier.
8. pharmaceutical composition as described in claim 7, wherein said composition is tablet, capsule, solution or injection form.
9. toxilic acid pyritinol crystal form A as claimed in claim 1 is for the preparation of the application in brain metabolism improving medicine.
10. apply as claimed in claim 9, wherein said medicinal application is in the improvement of the dizzy distending pain of cerebral trauma sequela, encephalitis or meningitis sequela etc., insomnia, hypomnesis, absent minded, emotional change; Or for cerebral arteriosclerosis, senile dementia mental symptom etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410260932.XA CN105153021A (en) | 2014-06-12 | 2014-06-12 | Crystal form of pyritinol maleate and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410260932.XA CN105153021A (en) | 2014-06-12 | 2014-06-12 | Crystal form of pyritinol maleate and preparation method thereof |
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| Publication Number | Publication Date |
|---|---|
| CN105153021A true CN105153021A (en) | 2015-12-16 |
Family
ID=54794120
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|---|---|---|---|
| CN201410260932.XA Pending CN105153021A (en) | 2014-06-12 | 2014-06-12 | Crystal form of pyritinol maleate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105153021A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062689A1 (en) * | 2003-01-08 | 2004-07-29 | Chiron Corporation | Stabilized aqueous compositions comprising tissue factor pathway inhibitor (tfpi) or tissue factor pathway inhibitor variant |
| CN101066266A (en) * | 2007-02-13 | 2007-11-07 | 广东中科药物研究有限公司 | Organic salt of pyritinol and its prepn process |
| CN103992268A (en) * | 2014-06-06 | 2014-08-20 | 浙江永宁药业股份有限公司 | Pyritinol maleate and preparation method thereof |
-
2014
- 2014-06-12 CN CN201410260932.XA patent/CN105153021A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062689A1 (en) * | 2003-01-08 | 2004-07-29 | Chiron Corporation | Stabilized aqueous compositions comprising tissue factor pathway inhibitor (tfpi) or tissue factor pathway inhibitor variant |
| CN101066266A (en) * | 2007-02-13 | 2007-11-07 | 广东中科药物研究有限公司 | Organic salt of pyritinol and its prepn process |
| CN103992268A (en) * | 2014-06-06 | 2014-08-20 | 浙江永宁药业股份有限公司 | Pyritinol maleate and preparation method thereof |
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Application publication date: 20151216 |