CN104693187A - Sunitinib L-malate crystal form gamma and preparation method thereof - Google Patents
Sunitinib L-malate crystal form gamma and preparation method thereof Download PDFInfo
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- CN104693187A CN104693187A CN201310737180.7A CN201310737180A CN104693187A CN 104693187 A CN104693187 A CN 104693187A CN 201310737180 A CN201310737180 A CN 201310737180A CN 104693187 A CN104693187 A CN 104693187A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses sunitinib L-malate crystal form gamma and a preparation method thereof. A diffraction diagram of X-ray powder of the sunitinib L-malate crystal form gamma has characteristic peaks on the position of 2theta+/-0.2, and 2theta is 7.51, 9.23, 9.60, 12.21, 12.84, 15.23, 16.03, 18.20, 18.90, 22.30 and 27.30. The preparation method of the sunitinib L-malate crystal form gamma comprises the following steps: dissolving free alkali of sunitinib and L-malic acid in organic solvent or in a mixture of the organic solvent and water to obtain a mixed solution; and placing the mixed solution into organic solvent at the temperature of -10 to 5 DEG C, carrying out the crystallization under a stirring condition, and filtering and drying a crystallized product to obtain the sunitinib L-malate crystal form gamma. The sunitinib L-malate crystal form gamma is relatively good in stability, the solubility in the water is remarkably improved compared with that of the Form I, the stability reaches the same level of the Form I in the market at present, and the preparation process is suitable for the large-scale industrial production.
Description
Technical field
The present invention relates to a kind of Sutent L MALIC ACID salt crystal formation λ and preparation method thereof.
Background technology
Sutent is the novel many targetings tyrosine kinase inhibitor (TKI) of one of being developed by Pfizer, be used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor, its structural formula is such as formula shown in I, chemical name is (Z)-N-[2-(diethylin) ethyl]-5-[(5-fluoro-2-dioxindole quinoline-3-subunit) methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamides;
At present for the different crystal forms of sunitinib malate, there is a large amount of reports.Patent WO2003016305, WO2009104021 and patent WO2010010454 disclose and protect Sutent L MALIC ACID crystal Form I to FormVII.Wherein, Form I has agent of low hygroscopicity, soluble in water.Further research finds that oxysuccinic acid Form I is thermodynamically more stable than Form II.Form I is preferential crystal formation.WO2009067686 protects Sutent racemization oxysuccinic acid Form A and B, Sutent half L MALIC ACID Form E and U.Therefore, solubleness sunitinib malate new crystal all preferably in a kind of stability and water is provided to provide.
Summary of the invention
The object of this invention is to provide a kind of Sutent L MALIC ACID salt crystal formation λ and preparation method thereof, Sutent L MALIC ACID salt crystal formation λ provided by the invention has relative good stability, in water solubleness comparatively Form I be significantly increased.
The Sutent L MALIC ACID salt with crystal formation λ provided by the present invention, its X-ray powder diffraction pattern has characteristic peak in 2 positions, θ ± 0.2, and described 2 θ are 7.51,9.23,9.60,12.21,12.84,15.23,16.03,18.20,18.90,22.30 and 27.30.
Above-mentioned Sutent L MALIC ACID salt crystal formation λ, its dsc is analyzed collection of illustrative plates (DSC) and have endotherm(ic)peak between 159 DEG C ~ 161 DEG C and 176 DEG C ~ 179 DEG C.
There is described in the present invention still further provides the preparation method of the Sutent L MALIC ACID salt of crystal formation λ, comprise the steps:
The free alkali of Sutent and L MALIC ACID are dissolved in the mixture of organic solvent or organic solvent and water and obtain mixed solution; Described mixed solution is added in the described organic solvent of-10 ~ 5 DEG C, carries out crystallization under agitation, after filtration and be drying to obtain described Sutent L MALIC ACID salt.
In above-mentioned preparation method, specifically described mixed solution can be added in the described organic solvent of-5 DEG C ,-10 ~-5 DEG C ,-5 ~ 0 DEG C or 0 ~-5 DEG C.
In above-mentioned preparation method, the free alkali of described Sutent and the mol ratio of described L MALIC ACID can be 0.9 ~ 1.5:1, specifically can be 1 ~ 1.2:1, specifically can be 1:1 or 1.2:1.
In above-mentioned preparation method, described organic solvent can be Isosorbide-5-Nitrae-dioxane or tetrahydrofuran (THF).
In above-mentioned preparation method, in the mixture of described organic solvent and water, the volume ratio of described organic solvent and described water can be 1 ~ 10:1, as 10:1.
In above-mentioned preparation method, vacuum drying mode is taked in described drying, described vacuum drying temperature can be 30 DEG C ~ 60 DEG C, specifically can be 30 DEG C, 40 DEG C or 60 DEG C, described vacuum drying vacuum tightness can be 0.02MPa ~ 0.10MPa, specifically can be 0.02MPa ~ 0.06MPa, 0.02MPa, 0.04MPa or 0.06MPa, the described vacuum drying time can be 0.5 hour ~ 24 hours, specifically can be 0.5 hour, 12 hours or 24 hours.
Sutent L MALIC ACID salt crystal formation λ provided by the invention, has relative good stability, in water solubleness comparatively Form I be significantly increased, its stability reaches the level that at present listing Form I is identical, and its preparation technology is applicable to large-scale industrial production.
Accompanying drawing explanation
Fig. 1 is dsc (DSC) spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the embodiment of the present invention 1.
Fig. 2 is X-ray powder diffraction (XRPD) spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the embodiment of the present invention 1.
Embodiment
The experimental technique used in following embodiment if no special instructions, is ordinary method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
In following embodiment, adopt the fusing point of DSC method to crystal to detect, testing tool is the Q2000DSC differential scanning calorimeter of TA company of the U.S., and concrete testing method is: N2 flow velocity is 120mL/min, and heat-up rate is 10 DEG C/min.
In following embodiment, adopt the crystal formation of xrd method to crystal to detect, the instrument of test is the brand-new D8ADVANCE X-ray diffractometer of Brooker AXS company; Concrete testing method is: voltage: 45kV, electric current: 40mA, slit: DS=2 °, SS=1/2 °, mask=15mm, RS=5.0mm; Scan pattern: continuous sweep; Sweep limit: 3 ° of-40 ° of 2 θ; Often walk gate time: 20s; Scanning total time: 6min.
The preparation of embodiment 1, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID (both mol ratios are 1:1) are dissolved in the mixing solutions of 20mL tetrahydrofuran (THF) and 2mL water, stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 20mL tetrahydrofuran (THF) of-5 DEG C ~ 0 DEG C, there is white precipitate in system.Dropwise, stir 1 hour at hierarchy of control temperature-5 DEG C, filter, obtain Sutent L-TARTARIC ACID salt crystal formation λ 4.5g after vacuum-drying (vacuum tightness is 0.06MPa, and temperature is 60 DEG C, and the time is 12 hours), yield is 85%.
The DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment as shown in Figure 1,
As shown in Figure 2, as seen from the figure, it has characteristic peak at 7.51,9.23,9.60,12.21,12.84,15.23,16.03,18.20,18.90,22.30 and 27.30 places to the XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment.
The preparation of embodiment 2, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4.8g Sutent and 1.34g L MALIC ACID (both mol ratios are 1.2:1) are dissolved in the mixing solutions of 20mL tetrahydrofuran (THF) and 2mL water, stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 20mL tetrahydrofuran (THF) of 0 DEG C, there is white precipitate in system.Dropwise, stir 2 hours at hierarchy of control temperature-5 DEG C ~ 0 DEG C, filter, after vacuum-drying (vacuum tightness is 0.06MPa, and temperature is 40 DEG C, and the time is 24 hours) Sutent L-TARTARIC ACID salt crystal formation λ 4.0g, yield is 75%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The preparation of embodiment 3, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID are dissolved in 40mL tetrahydrofuran (THF), stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 20mL tetrahydrofuran (THF) of-5 DEG C, there is white precipitate in system.Dropwise, stir 3 hours at hierarchy of control temperature-5 DEG C ~ 0 DEG C, filter, after vacuum-drying (vacuum tightness is 0.06MPa, and temperature is 60 DEG C, and the time is 0.5 hour) Sutent L-TARTARIC ACID salt crystal formation λ 3.7g, yield is 71%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The preparation of embodiment 4, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID are dissolved in 50mL1, in 4-dioxane, stirs and heat and make it dissolve.Above mixed solution is slowly instilled the 10mL1 meeting in advance and be as cold as-3 DEG C, in 4-dioxane, there is white precipitate in system.Dropwise, stir 4 hours at hierarchy of control temperature-5 DEG C ~ 0 DEG C, filter, after vacuum-drying (vacuum tightness is 0.02MPa, and temperature is 30 DEG C, and the time is 24 hours) Sutent L-TARTARIC ACID salt crystal formation λ 4.0g, yield is 75%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The preparation of embodiment 5, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID are dissolved in the mixing solutions of 10mL tetrahydrofuran (THF) and 10mL water, stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 10mL tetrahydrofuran (THF) of-2 DEG C, there is white precipitate in system.Dropwise, stir 2 hours at hierarchy of control temperature-5 DEG C ~ 0 DEG C, filter, after vacuum-drying (vacuum tightness is 0.04MPa, and temperature is 30 DEG C, and the time is 24 hours) Sutent L-TARTARIC ACID salt crystal formation λ 2.2g, yield is 41%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The preparation of embodiment 6, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID are dissolved in the mixing solutions of 20mL tetrahydrofuran (THF) and 2mL water, stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 40mL tetrahydrofuran (THF) of-10 DEG C ~-5 DEG C, there is white precipitate in system.Dropwise, stir 4 hours at hierarchy of control temperature-10 DEG C ~-5 DEG C, filter, obtain Sutent L-TARTARIC ACID salt crystal formation λ 4.1g after vacuum-drying (vacuum tightness is 0.06MPa, and temperature is 60 DEG C, and the time is 12 hours), yield is 77%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The preparation of embodiment 7, Sutent L MALIC ACID salt crystal formation λ
The free alkali of 4g Sutent and 1.34g L MALIC ACID are dissolved in the mixing solutions of 20mL tetrahydrofuran (THF) and 2mL water, stirs and heat and make it dissolve.Slowly being instilled by above mixed solution to meet in advance and be as cold as in the 10mL tetrahydrofuran (THF) of 0 DEG C ~ 5 DEG C, there is white precipitate in system.Dropwise, stir 4 hours at hierarchy of control temperature 0 DEG C ~ 5 DEG C, filter, obtain Sutent L-TARTARIC ACID salt crystal formation λ 3.5g after vacuum-drying (vacuum tightness is 004MPa, and temperature is 60 DEG C, and the time is 12 hours), yield is 66%.
After testing, the DSC spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared of the present embodiment and Fig. 1 basically identical.
The XRPD spectrogram of Sutent L MALIC ACID salt crystal formation λ prepared by the present embodiment and Fig. 2 basically identical.
The solubleness test of the Sutent L MALIC ACID salt crystal formation λ of embodiment 8, embodiment 1 preparation
Sutent L MALIC ACID salt crystal formation λ and Sutent L MALIC ACID salt crystal formation I correlation data of solubleness in water of embodiment 1 preparation are as shown in table 1.
Sutent L MALIC ACID salt solubility testing method is as follows: in closed glass container, add the sample of 5mL water and 1g Sutent L MALIC ACID different crystal forms (λ and I), shake 1 hour in the thermostat water bath presetting temperature, rapid filtration system afterwards.Filtrate is concentrated into after doing and weighs.The Calculation of Solubility of Sutent L MALIC ACID different crystal forms as shown in the formula:
Solubleness=X mg/5mL (wherein X is the concentrated dry rear solid weight numerical value of filtrate).
Table 1 Sutent L MALIC ACID salt crystal formation I and crystal formation λ solubleness correlation data (mg/mL) in water
As can be seen from the data in table 1, the solubleness under the differing temps of Sutent L MALIC ACID salt crystal formation λ in water is all better than Buddhist nun for Buddhist nun's L MALIC ACID salt crystal formation I.
The stability test of the Sutent L MALIC ACID salt crystal formation λ of embodiment 9, embodiment 1 preparation
The stability of Sutent L MALIC ACID salt crystal formation λ under room temperature (25 DEG C) stores prepared by embodiment 1 is as shown in table 2.
Sutent L MALIC ACID salt different crystal forms sample, tetrafluoroethylene bag is used to vacuumize preservation, every bag of sample 100mg, sample storage in 25 DEG C, in the constant humidity cabinet of 75% humidity, a bag respective sample is taken out at the time point of setting, then carry out HPLC and detect its purity (HPLC testing conditions: Agilent liquid chromatograph, chromatographic column: ZORBAXEclipse XDB-C18150mm*4.6mm, 5um; Mobile phase A: 0.1% trifluoroacetic acid aqueous solution, Mobile phase B: 0.1% trifluoroacetic acid acetonitrile solution; Determined wavelength: 250nm; Flow velocity: 1mL/min).
The stability correlation data of table 2 Sutent L MALIC ACID salt crystal formation I and crystal formation λ under room temperature (25 DEG C) stores
As can be seen from the data in table 2, at room temperature its purity and crystal formation all have good storage stability to Sutent L MALIC ACID salt crystal formation λ crystal formation.
Claims (8)
1. one kind has the Sutent L MALIC ACID salt of crystal formation λ, it is characterized in that: its X-ray powder diffraction pattern has characteristic peak in 2 positions, θ ± 0.2, described 2 θ are 7.51,9.23,9.60,12.21,12.84,15.23,16.03,18.20,18.90,22.30 and 27.30.
2. Sutent L MALIC ACID salt according to claim 1, is characterized in that: the dsc of described Sutent L MALIC ACID salt is analyzed collection of illustrative plates and have endotherm(ic)peak between 159 DEG C ~ 161 DEG C and 176 DEG C ~ 179 DEG C.
3. the preparation method of Sutent L MALIC ACID salt described in claim 1 or 2, comprises the steps:
The free alkali of Sutent and L MALIC ACID are dissolved in the mixture of organic solvent or organic solvent and water and obtain mixed solution; Described mixed solution is added in the described organic solvent of-10 ~ 5 DEG C, carries out crystallization under agitation, after filtration with drying after namely obtain described in there is the Sutent L MALIC ACID salt of crystal formation λ.
4. preparation method according to claim 3, is characterized in that: the free alkali of described Sutent and the mol ratio of described L MALIC ACID are 0.9 ~ 1.5:1.
5. the preparation method according to claim 3 or 4, is characterized in that: described organic solvent is Isosorbide-5-Nitrae-dioxane or tetrahydrofuran (THF).
6. preparation method according to claim 5, is characterized in that: in the mixture of described organic solvent and water, and the volume ratio of described organic solvent and described water is 1 ~ 10:1.
7. the preparation method according to any one of claim 3-6, it is characterized in that: vacuum drying mode is taked in described drying, described vacuum drying temperature is 30 DEG C ~ 60 DEG C, described vacuum drying vacuum tightness can be 0.02MPa ~ 0.10MPa, and the described vacuum drying time is 0.5 hour ~ 24 hours.
8. a pharmaceutical composition, it comprises Sutent L MALIC ACID salt described in claim 1 or 2 and one or more pharmaceutically acceptable carrier or vehicle.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020216450A1 (en) | 2019-04-25 | 2020-10-29 | Synthon B.V. | Pharmaceutical composition comprising amorphous sunitinib |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543462A (en) * | 2001-08-15 | 2004-11-03 | �������Ŷ���Լ��������˾ | Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof |
| WO2009156837A2 (en) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Amorphous form of a 3-pyrrole substituted 2-indolinone malate salt |
| CN101983195A (en) * | 2008-02-21 | 2011-03-02 | 基因里克斯(英国)有限公司 | Novel polymorphs and processes for their preparation |
| WO2011092664A1 (en) * | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | Crystalline forms of l-malic acid salt of sunitinib |
| CN102164913A (en) * | 2008-07-24 | 2011-08-24 | 麦迪凯姆股份公司 | Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102203085A (en) * | 2008-07-10 | 2011-09-28 | 基因里克斯(英国)有限公司 | Processes for the preparation of crystalline forms of sunitinib malate |
| CN102272124A (en) * | 2008-11-13 | 2011-12-07 | 力奇制药公司 | New crystal form of sunitinib malate |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
-
2013
- 2013-12-26 CN CN201310737180.7A patent/CN104693187A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1543462A (en) * | 2001-08-15 | 2004-11-03 | �������Ŷ���Լ��������˾ | Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof |
| CN101983195A (en) * | 2008-02-21 | 2011-03-02 | 基因里克斯(英国)有限公司 | Novel polymorphs and processes for their preparation |
| WO2009156837A2 (en) * | 2008-06-26 | 2009-12-30 | Medichem, S.A. | Amorphous form of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102203085A (en) * | 2008-07-10 | 2011-09-28 | 基因里克斯(英国)有限公司 | Processes for the preparation of crystalline forms of sunitinib malate |
| CN102164913A (en) * | 2008-07-24 | 2011-08-24 | 麦迪凯姆股份公司 | Crystalline forms of a 3-pyrrole substituted 2-indolinone malate salt |
| CN102272124A (en) * | 2008-11-13 | 2011-12-07 | 力奇制药公司 | New crystal form of sunitinib malate |
| WO2011092664A1 (en) * | 2010-01-29 | 2011-08-04 | Ranbaxy Laboratories Limited | Crystalline forms of l-malic acid salt of sunitinib |
| WO2012059941A1 (en) * | 2010-11-04 | 2012-05-10 | Ind-Swift Laboratories Limited | Process for preparation of sunitinib malate and salts thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020216450A1 (en) | 2019-04-25 | 2020-10-29 | Synthon B.V. | Pharmaceutical composition comprising amorphous sunitinib |
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Effective date of registration: 20161209 Address after: Taoyuan County of Ninghai city of Ningbo province Zhejiang 315615 Street No. 2 Taoyuan Road, building 9 Branch Center Applicant after: Ningbo Ainuo Medical Technology Co Ltd Address before: 100085 Beijing, Haidian District venture Road No. 36 501X Applicant before: Ainger century biotechnology (Beijing) Co., Ltd. |
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