CN104926800A - Crystal form of afatinib di-meleate and method for preparing crystal form - Google Patents
Crystal form of afatinib di-meleate and method for preparing crystal form Download PDFInfo
- Publication number
- CN104926800A CN104926800A CN201510357934.5A CN201510357934A CN104926800A CN 104926800 A CN104926800 A CN 104926800A CN 201510357934 A CN201510357934 A CN 201510357934A CN 104926800 A CN104926800 A CN 104926800A
- Authority
- CN
- China
- Prior art keywords
- crystallized form
- form according
- base
- crystal form
- buddhist nun
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crystal form of afatinib di-meleate, a method for preparing the crystal form, pharmaceutical composition with the same and application of the pharmaceutical composition. X-ray powder diffraction spectra of the crystal form have characteristic peaks at diffraction angles 2theta of 4.9+/-0.2 degrees, 10.5+/-0.2 degrees, 12.8+/-0.2 degrees, 17.2+/-0.2 degrees and 19.8+/-0.2 degrees, and a melting point of the crystal form is 168.68. The crystal form, the method, the pharmaceutical composition and the application have the advantage that the pharmaceutical composition can be applied to anti-cancer medicine.
Description
Technical field
The present invention relates to crystallized form of a kind of quinazoline ditosylate salt cancer therapy drug and preparation method thereof, belong to field of pharmaceutical chemistry technology.
Background technology
Ah method is for Buddhist nun's 2-maleate, chemistry 4-by name [(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline, (2Z)-(E)-butenedioic acid (1:2), its structural formula is as follows
Ah method is the irreversible inhibitor of a kind of EGF-R ELISA (EGFR) and people's epidermal receptor Tyrosylprotein kinase (HER2) for Buddhist nun's 2-maleate, be first for the lung cancer therapy medicine after EGFR inhibitor Endodontic failure, can be used for the treatment of advanced Non-small cell lung and advanced breast cancer, intestinal cancer.
International Publication No. WO2005037824A discloses the non-solvated compound (being called crystal form A) that Ah method replaces Buddhist nun's 2-maleate and a kind of crystallization thereof, has endotherm(ic)peak at its DSC collection of illustrative plates shows 178 DEG C.It is needle crystal that WO2009147238A discloses this crystal formation, and the process preparing solid oral dosage form exists following challenge: the easy sliver of water sensitivity, low bulk density, poor fluidity, direct compression or lamination, poor, the easy sticking of compressibility etc.The Ah method that WO2012121764A discloses a kind of crystallization, for Buddhist nun's 2-maleate (being called crystal form B), has exothermic peak, has secondary endotherm(ic)peak at 156.8 DEG C, has main endotherm(ic)peak, its poor heat stability as seen at 173.9 DEG C at its DSC collection of illustrative plates shows 125.9 DEG C.WO2013052157A discloses Ah method for Buddhist nun's 2-maleate crystal C, D, E, wherein crystal C may be solvate, its DSC has exothermic peak at 40 ~ 95 DEG C, there is exothermic peak at 112.38 DEG C, have exothermic peak at 161.39 DEG C, have endotherm(ic)peak at 172.91 DEG C, crystal formation D may be anhydrate, and its DSC has endotherm(ic)peak at 186.18 DEG C, and crystal formation E is trihydrate, water content is 5.9 ~ 8.1%, and higher moisture content is to humidity sensitive.It is 133.7 DEG C that WO2015007206 discloses Ah method for Buddhist nun's 2-maleate crystal formation N, its TGA display decomposition temperature, and points out that Ah method all has comparatively serious water absorbability for Buddhist nun's 2-maleate crystal form B, C, D, E further.
Summary of the invention
The invention provides a kind of new 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino the crystallized form of-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline 2-maleate (Ah method is for Buddhist nun's 2-maleate), be called crystal formation H.
Ah method of the present invention is that 4.9 ± 0.2 °, 10.5 ± 0.2 °, 12.8 ± 0.2 °, 17.2 ± 0.2 °, 19.8 ± 0.2 ° places have characteristic peak for the X-ray powder diffraction of Buddhist nun's 2-maleate crystal formation H at diffraction angle 2 θ.
Further, Ah method of the present invention is that 4.9 ± 0.2 °, 6.5 ± 0.2 °, 10.5 ± 0.2 °, 12.8 ± 0.2 °, 17.2 ± 0.2 °, 19.8 ± 0.2 °, 21.1 ± 0.2 °, 25.4 ± 0.2 ° places have characteristic peak for the X-ray powder diffraction of Buddhist nun's 2-maleate crystal formation H at diffraction angle 2 θ.
Further, Ah method of the present invention replaces the X-ray powder diffraction of Buddhist nun's 2-maleate crystal formation H as shown in Figure 1.
Again further, Ah method of the present invention is that 157 ~ 171 DEG C of places have endotherm(ic)peak for the DSC collection of illustrative plates of Buddhist nun's 2-maleate crystal formation H in temperature.
Again further, Ah method of the present invention replaces the DSC collection of illustrative plates of Buddhist nun's 2-maleate crystal formation H as shown in Figure 2.
Ah method of the present invention is anhydrate for Buddhist nun's 2-maleate crystal formation.
Present invention also offers and a kind ofly prepare Ah method of the present invention for the method for Buddhist nun's 2-maleate crystal formation H, comprise the following steps: 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-{4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline joins heated and stirred in organic solvent and dissolve, after toxilic acid organic solvent dissolution, be added dropwise in above-mentioned solution, after dropwising, Temperature fall to 20 ± 2 DEG C, then cool to 0 ± 2 DEG C and continue stirring 1 ~ 6 hour, suction filtration, vacuum-drying, wherein, described organic solvent is selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride or N, N-diformamide, ethyl acetate.
In some embodiments of the present invention, the time of described Temperature fall to 20 ± 2 DEG C is within 2 hours, and described continuation churning time is 2 hours
In some embodiments of the present invention, described vacuum drying temperature is 30 ~ 50 DEG C, preferably 40 DEG C, and the described vacuum-drying time is 1 ~ 10 hour, preferably 4 hours, and described vacuum drying pressure is-10 ~ 20Pa.
Present invention also offers the application of a kind of Ah method for Buddhist nun's 2-maleate crystal formation H, for the preparation of the medicine of Therapeutic cancer, wherein, described cancer is selected from nonsmall-cell lung cancer, advanced breast cancer or intestinal cancer, preferred nonsmall-cell lung cancer.
Find after deliberation, Ah method of the present invention is anhydrate for Buddhist nun two toxilic acid crystal formation H, there is excellent chemical purity, mobility, solvability and stability (as stored, degrading, turn crystalline substance, water absorbability and low residue solvent), its preparation method operation steps is simple, without the need to specific installation, production cost is low, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (PXRD) collection of illustrative plates of Ah method of the present invention for Buddhist nun's 2-maleate crystal formation H.
Fig. 2 is means of differential scanning calorimetry (DSC) collection of illustrative plates of Ah method of the present invention for Buddhist nun's 2-maleate crystal formation H.
Specific embodiments
Explain further below by example and the present invention is described, but not limiting the present invention in any form.Any type of equivalent substituting all falls into protection scope of the present invention.
Embodiment 1 Ah method is for the preparation of Buddhist nun's 2-maleate crystal formation H
4g (8.23mmol) Ah method is dissolved in 40ml ethyl acetate for Buddhist nun's alkali, be heated to 65 DEG C of dissolvings, again ethyl acetate (5ml) solution of 2g (17.3mmol) toxilic acid is slowly added dropwise in above-mentioned solution, dropwise rear be naturally down to room temperature after cool rapidly to 0 DEG C, stir 2 hours, separate out a large amount of solid, suction filtration obtains off-white powder, 40 DEG C of vacuum-drying 4 hours, purity (HPLC:99.55%).
Embodiment 2 Ah method is for the preparation of Buddhist nun's 2-maleate crystal formation H
10g (20.58mmol) Ah method is dissolved in 100ml ethyl acetate for Buddhist nun's alkali, be heated to 65 DEG C of dissolvings, again ethyl acetate (10ml) solution of 5g (43.08mmol) toxilic acid is slowly added dropwise in above-mentioned solution, dropwise rear be naturally down to room temperature after cool rapidly to 0 DEG C, stir 2 hours, separate out a large amount of solid, suction filtration obtains off-white powder, 40 DEG C of vacuum-drying 4 hours, purity (HPLC:99.74%).
Embodiment 3 Ah method is for the preparation of Buddhist nun's 2-maleate crystal formation H
50g (102.9mmol) Ah method is dissolved in 500ml ethyl acetate for Buddhist nun's alkali, be heated to 65 DEG C of dissolvings, again ethyl acetate (50ml) solution of 24.5g (211.0mmol) toxilic acid is slowly added dropwise in above-mentioned solution, dropwise rear be naturally down to room temperature after cool rapidly to 0 DEG C, stir 2 hours, separate out a large amount of solid, suction filtration obtains off-white powder, 40 DEG C of vacuum-drying 6 hours, purity (HPLC:99.77%).
Embodiment 4 Ah method is for the preparation of Buddhist nun's 2-maleate crystal formation H
Replace Buddhist nun's alkali in 3L there-necked flask 200g (411.5mmol) Ah method, add 2L ethyl acetate, be heated to 65 DEG C of dissolvings, again ethyl acetate (200ml) solution of 97.9g (843.6mmol) toxilic acid is slowly added dropwise in above-mentioned solution, dropwise rear be naturally down to room temperature after cool rapidly to 0 DEG C, stir 2 hours, separate out a large amount of solid, suction filtration obtains off-white powder, 40 DEG C of vacuum-drying 8 hours, purity (HPLC:99.72%).
Ah method is for the sign of Buddhist nun's 2-maleate crystal formation H
PXRD instrument: Bruker D8ADVANCE type X-ray diffractometer; Test condition: light source is Cu target, K α line, 40kV, 40mA; Step-length is 0.02 °; Sweep velocity is 8 °/min; Sweep limit: 3 ° ~ 45 °.
Ah method replaces the X-ray powder diffraction of Buddhist nun's 2-maleate crystal formation H as shown in Figure 1, and it has following characteristic peak:
DSC instrument: TA Q20 differential scanning calorimeter; Test condition: balance after 130 DEG C, with 5 DEG C/min ramp to 200 DEG C.
Ah method replaces the DSC of Buddhist nun's 2-maleate crystal formation H as shown in Figure 2, and it has endotherm(ic)peak temperature 157.84 DEG C ~ 170.56 DEG C, and peak value is 168.62 DEG C.
Comparative example 1
Ah method is prepared respectively for Buddhist nun's 2-maleate crystal form A and crystal formation N according to method disclosed in WO2005037824A and WO2015007206A.
(1) solubility test
Precision takes Ah method for Buddhist nun's 2-maleate crystal form A, each 5mg of N and H, and the damping fluid dripping purified water and different pH value at temperature 25 DEG C all dissolves to sample, measures solubleness.It the results are shown in Table 1.
Table 1
| Condition | Crystal form A solubleness | Crystal formation N solubleness | Crystal formation H solubleness |
| Water | ＞50mg/mL | ＞50mg/mL | ＞50mg/mL |
| PH 1 (0.1M hydrochloric acid) | ＞50mg/mL | ＞50mg/mL | ＞50mg/mL |
| PH 4 (McIlvaine damping fluid) | ＞50mg/mL | ＞50mg/mL | ＞50mg/mL |
| PH 6.8 (McIlvaine damping fluid) | ＞16mg/mL | ＞18mg/mL | ＞20mg/mL |
| PH8.0 (Sorensen damping fluid) | 0.033mg/mL | 0.036mg/mL | 0.037mg/mL |
(2) Ah method is for Buddhist nun's 2-maleate oral tablet
With reference to CN200980121080.3 preparation method; respectively Ah method is made the agent of oral film garment piece for Buddhist nun's 2-maleate crystal form A, crystal formation N, crystal formation H tri-kinds of Ah methods for Buddhist nun's salt: calculate inventory with batch 1000; get respectively each crystal formation bulk drug with 1% Magnesium Stearate mix; use dry granulating machine; with pinch roller gap 1mm and compaction force 10kN/cm operating parameter, material is pressed into sheet; the whole grain of 60 mesh sieve; gained particle mixes with leftover materials; by 360mg/ sheet; use Rotarytabletpress, be pressed into tablet with 10mm shallow concave punch.Its prescription composition is in table 2, and its tablet measurement result is in table 3.
Table 2
| Crystal formation | Weight percent (%/sheet) | Crystal form A (mg/ sheet) | Crystal formation N (mg/ sheet) | Crystal formation H (mg/ sheet) |
| Ah method is for Buddhist nun's 2-maleate | 16.42 | 59.12 | 59.12 | 59.12 |
| Relative to " Ah method is for Buddhist nun's alkali " | 11.00 | 40.00 | 40.00 | 40.00 |
| Spherolac 100 | 68.81 | 247.72 | 247.72 | 247.72 |
| Microcrystalline Cellulose | 10.27 | 36.96 | 36.96 | 36.96 |
| Crospovidone | 2.00 | 7.20 | 7.20 | 7.20 |
| Colloidal silica anhydrous | 0.50 | 1.80 | 1.80 | 1.80 |
| Magnesium Stearate | 2.00 | 7.20 | 7.20 | 7.20 |
| Amount to | 100.00 | 360.00 | 360.00 | 360.00 |
Table 3
Result shows, in crystal form A, crystal formation N and crystal formation H table 2, tablet respectively measures equal no significant difference, meets the requirements.It should be noted that in the identical compression force situation of employing, there is sticking to a certain degree or wall sticking phenomenon in the tablet of crystal form A, crystal formation N and H does not then have.
Claims (10)
1. 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-{ [4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino the crystallized form of-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline 2-maleate, it is characterized in that, its X-ray powder diffraction is that 4.9 ± 0.2 °, 10.5 ± 0.2 °, 12.8 ± 0.2 °, 17.2 ± 0.2 °, 19.8 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
2. crystallized form according to claim 1, it is characterized in that, its X-ray powder diffraction is that 4.9 ± 0.2 °, 6.5 ± 0.2 °, 10.5 ± 0.2 °, 12.8 ± 0.2 °, 17.2 ± 0.2 °, 19.8 ± 0.2 °, 21.1 ± 0.2 °, 25.4 ± 0.2 ° places have characteristic peak at diffraction angle 2 θ.
3. crystallized form according to claim 1, is characterized in that, its X-ray powder diffraction as shown in Figure 1.
4. crystallized form according to claim 1, is characterized in that, its DSC collection of illustrative plates is that 157 ~ 171 DEG C of places have endotherm(ic)peak in temperature.
5. crystallized form according to claim 1, is characterized in that, its DSC collection of illustrative plates as shown in Figure 2.
6. crystallized form according to claim 1, is characterized in that, described crystallized form is anhydrate.
7. prepare the method for anhydrate crystallized form according to claim 1 for one kind, it is characterized in that, comprise the steps: 4-[(the chloro-4-fluorophenyl of 3-) is amino]-6-{4-[4-(N, N-dimethylamino)-1-oxo-2-butylene-1-base] amino-7-[(S)-(tetrahydrofuran (THF)-3-base) oxygen base] quinazoline joins heated and stirred in organic solvent and dissolve, after toxilic acid organic solvent dissolution, be added dropwise in above-mentioned solution, after dropwising, Temperature fall to 20 ± 2 DEG C, then cool to 0 ± 2 DEG C and continue stirring 1 ~ 6 hour, suction filtration, vacuum-drying, wherein, described organic solvent is selected from methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), ethyl acetate, methylene dichloride or N, N-diformamide, ethyl acetate.
8. method according to claim 7, is characterized in that, the time of described Temperature fall to 20 ± 2 DEG C is within 2 hours, and described continuation churning time is 2 hours.
9. method according to claim 7, is characterized in that, described vacuum drying temperature is 30 ~ 50 DEG C, preferably 40 DEG C, and the described vacuum-drying time is 1 ~ 10 hour, preferably 4 hours, and described vacuum drying pressure is-10 ~ 20Pa.
10. crystallized form according to claim 1 is preparing the application in Therapeutic cancer medicine, and wherein, described cancer is selected from nonsmall-cell lung cancer, advanced breast cancer or intestinal cancer, preferred nonsmall-cell lung cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510357934.5A CN104926800A (en) | 2015-06-26 | 2015-06-26 | Crystal form of afatinib di-meleate and method for preparing crystal form |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510357934.5A CN104926800A (en) | 2015-06-26 | 2015-06-26 | Crystal form of afatinib di-meleate and method for preparing crystal form |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104926800A true CN104926800A (en) | 2015-09-23 |
Family
ID=54114253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510357934.5A Pending CN104926800A (en) | 2015-06-26 | 2015-06-26 | Crystal form of afatinib di-meleate and method for preparing crystal form |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104926800A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2508521B1 (en) | 2003-10-17 | 2015-12-30 | Boehringer Ingelheim International GmbH | Dimaleat of an amino crotonyl compound and method of production thereof |
| WO2016166720A3 (en) * | 2015-04-17 | 2017-02-02 | Hetero Research Foundation | Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives |
| WO2017093789A1 (en) * | 2015-12-03 | 2017-06-08 | Mylan Laboratories Ltd. | Polymorphic forms of afatinib dimaleate |
| CN109824657A (en) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application |
| CN110563710A (en) * | 2019-09-21 | 2019-12-13 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402631A (en) * | 2003-10-17 | 2009-04-08 | 贝林格尔.英格海姆国际有限公司 | Amino quinazoline 2-maleate, production method and uses thereof |
| WO2013052157A1 (en) * | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN104447713A (en) * | 2014-11-18 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of afatinib compound |
| US9012464B2 (en) * | 2010-11-25 | 2015-04-21 | Ratiopharm Gmbh | Salts and polymorphic forms of Afatinib |
-
2015
- 2015-06-26 CN CN201510357934.5A patent/CN104926800A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101402631A (en) * | 2003-10-17 | 2009-04-08 | 贝林格尔.英格海姆国际有限公司 | Amino quinazoline 2-maleate, production method and uses thereof |
| US9012464B2 (en) * | 2010-11-25 | 2015-04-21 | Ratiopharm Gmbh | Salts and polymorphic forms of Afatinib |
| WO2013052157A1 (en) * | 2011-10-06 | 2013-04-11 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN104447713A (en) * | 2014-11-18 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of afatinib compound |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2508521B1 (en) | 2003-10-17 | 2015-12-30 | Boehringer Ingelheim International GmbH | Dimaleat of an amino crotonyl compound and method of production thereof |
| WO2016166720A3 (en) * | 2015-04-17 | 2017-02-02 | Hetero Research Foundation | Polymorphs of afatinib and its salts and process for the preparation of quinazolinyl derivatives |
| US10329281B2 (en) | 2015-04-17 | 2019-06-25 | Hetero Labs Ltd | Polymorphs and process for the preparation of quinazolinyl derivatives |
| WO2017093789A1 (en) * | 2015-12-03 | 2017-06-08 | Mylan Laboratories Ltd. | Polymorphic forms of afatinib dimaleate |
| CN109824657A (en) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | Two maleic acid Afatinib novel crystal forms of one kind and its preparation method and application |
| CN110563710A (en) * | 2019-09-21 | 2019-12-13 | 广东安诺药业股份有限公司 | Preparation method of afatinib maleate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018220045B2 (en) | C-met modulator pharmaceutical compositions | |
| US8884013B2 (en) | Polymorphs of Dasatinib, preparation methods and pharmaceutical compositions thereof | |
| US10954223B2 (en) | Canagliflozin monohydrate and its crystalline forms, preparation methods and uses thereof | |
| CN104926800A (en) | Crystal form of afatinib di-meleate and method for preparing crystal form | |
| CN102086195B (en) | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof | |
| US20220267299A1 (en) | New crystalline forms of n-(3-(2-(2-hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methvlphenyl)-2 (trifluoromethyl)isonicotinamide as raf inhibitors for the treatment of cancer | |
| AU2014283231B2 (en) | Amorphous Letermovir and solid pharmaceutical formulations thereof for oral administration | |
| WO2009025875A1 (en) | Stable formulations of crystalline erlotinib hcl | |
| CN104829523B (en) | Rui Gefeini salt and its crystal formation, preparation method | |
| CN112142679B (en) | Gefitinib and vanilloid eutectic methanol solvate and preparation method thereof | |
| AU2013330603B2 (en) | Monohydrate crystal of fimasartan potassium salt, method for preparing same, and pharmacological composition comprising same | |
| EP1948618A1 (en) | Crystalline rosuvastatin calcium | |
| CN108558655B (en) | 2- [4- (4-chlorobenzoyl) phenoxy ] -2-methylpropanoic acid polymorphic substance, preparation method and pharmaceutical composition thereof | |
| CN102250084A (en) | Dasatinib polymorphic substance as well as preparation method and pharmaceutical composition thereof | |
| CN106810490A (en) | A kind of crystal formation of biaryl compound and its preparation method and application | |
| CN104788435A (en) | I-type crystal of dibenzenesulfonate of inhibitor of protein tyrosine kinase | |
| EP2832723B1 (en) | Stabilised amorphous forms of Saxagliptin | |
| US20090124642A1 (en) | Crystalline forms of Erlotinib HCI and formulations thereof | |
| CN106188012A (en) | A kind of A Lishatan ester crystallization and preparation method thereof and the pharmaceutical composition containing this crystallization | |
| CN102372673A (en) | Blonanserin crystallization and preparation method thereof | |
| JP5589097B2 (en) | Dasatinib polycrystal, preparation method thereof and drug composition | |
| US20210122737A1 (en) | Novel polymorph of flibanserin and preparation method thereof and use of same | |
| CN104829629A (en) | Sulfonamide-containing tetrahydrothieno[2,3-c] pyridine derivatives, preparing method thereof and uses of the derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150923 |
|
| WD01 | Invention patent application deemed withdrawn after publication |