CN104725314A - New crystal form of Ivacaftor and preparation method thereof - Google Patents
New crystal form of Ivacaftor and preparation method thereof Download PDFInfo
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- CN104725314A CN104725314A CN201510126289.6A CN201510126289A CN104725314A CN 104725314 A CN104725314 A CN 104725314A CN 201510126289 A CN201510126289 A CN 201510126289A CN 104725314 A CN104725314 A CN 104725314A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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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
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Abstract
The invention discloses a new crystal form of Ivacaftor and a preparation method thereof, belonging to the technical field of medicine chemical industry. The preparation method comprises the following steps: dispersing Ivacaftor in a crystal solvent, dissolving the solid by heating, slowly cooling to crystallize, filtering, and drying to obtain the Ivacaftor crystal. The new crystal form powder has characteristic peaks in the X-ray diffractogram when the 2theta angle is 4.082+/-0.2 degrees, 6.135+/-0.2 degrees, 7.563+/-0.2 degrees, 8.374+/-0.2 degrees, 9.184+/-0.2 degrees, 11.705+/-0.2 degrees, 12.306+/-0.2 degrees, 17.858+/-0.2 degrees, 18.759+/-0.2 degrees and 20.92+/-0.2 degrees. The new crystal form of Ivacaftor has the advantages of high purity and favorable stability. The preparation method has the advantages of simple technique, high product yield and environment friendliness.
Description
Technical field
New crystal D that the present invention relates to a kind of Ivacaftor and preparation method thereof, belongs to pharmaceutical chemistry technical field.
Background introduction
Ivacaftor, in FDA approval listing on January 31st, 2012, is used for the treatment of cystic fibrosis (cysticfibrosis, CF), is developed, trade(brand)name Kalydeco by Vertex Pharmaceuticals company.Cystic fibrosis is a kind of genetic diseases, mainly raises as principal character so that Chronic Obstructive Pulmonary pathology, pancreatic exocrine insufficiency and sweat ionogen are abnormal.Cystic fibrosis is the heredopathia in modal impact existence life-span in white man, by cystic fibrosis transmembrane conductance regulator (cystic firbrosis transmembraneconductance regulator, CFTR) sudden change produces, the defect of CFTR plays a significant role in the generating process of this disease, ivacaftor is then used for reaching therapeutic purpose by what improve CFTR just, this oral medicine can increase the open hour of cell surface CFTR passage, experiment in vitro proves, ivacaftor can improve the chlorion transport activity of G551D-CFTR albumen, thus on source, block the morbidity of CF.The structural formula of Ivacaftor is as follows:
Material owing to affecting by various factors, makes in molecule or intermolecular bonding mode changes when crystallization, cause molecule or atom different in lattice vacancy arrangement, form different crystalline structure.The different crystal forms of same medicine may have remarkable difference in outward appearance, solubleness, fusing point, dissolution rate, biological effectiveness etc., thus have impact on the stability of medicine, bioavailability and curative effect.Therefore, study and grasp polymorph in pharmaceuticals and character thereof, contributing to the physicochemical stability ensureing medicine, improving the bioavailability of medicine, promote curative effect.
The patent WO2007079139 that Vertex Pharmaceuticals company delivers discloses two kinds of crystal formations of Ivacaftor the earliest: obtain crystal form A by fusion-crystallization and obtain crystal form B by solvent crystal, prepare crystal form A and need high-temperature fusion, energy consumption is high, the time of preparing crystal form B total is long, and efficiency is low.Patent WO2009038683 subsequently discloses the multiple crystalline compounds of Ivacaftor, comprises the salt of Ivacaftor, solvate, cocrystallization and hydrate, amounts to 16 kinds of crystal formations.WO2011116397 discloses the crystal C of Ivacaftor, is obtained by solvent crystal, has the shortcoming that preparation cycle is long equally.WO2013158121 studies further to the salt of Ivacaftor, solvate, cocrystallization and hydrate crystal forms, discloses 19 kinds of new crystal altogether.
The present inventor, in process of experimental, finds that Ivacaftor also exists other new crystal, and be different from existing disclosed crystal formation, called after Ivacaftor crystal formation D of the present invention, for the application of Ivacaftor provides more choices.The present invention also provides the crystallization method of Ivacaftor new crystal D, and the method technique is simple, product yield is high, and obtains that purity is high, the crystal of good stability.
Summary of the invention
The object of this invention is to provide a kind of Ivacaftor new crystal D and preparation method thereof, this crystal form purity is high, good stability, and this preparation method's technique is simple, product yield is high, environmental friendliness.
The new crystal D powder x-ray diffraction figure of Ivacaftor of the present invention represents to have characteristic peak at 4.082 ± 0.2 °, 6.135 ± 0.2 °, 7.563 ± 0.2 °, 8.374 ± 0.2 °, 9.184 ± 0.2 °, 11.705 ± 0.2 °, 12.306 ± 0.2 °, 17.858 ± 0.2 °, 18.759 ± 0.2 °, 20.92 ± 0.2 ° places with 2 θ angles.
In the powder x-ray diffraction figure of the new crystal D of Ivacaftor of the present invention, 2 θ angles at the peaks at 4.082 ± 0.2 ° of places by force than being 100%, 2 θ angles 7.563 ± 0.2 ° place peaks by force than being not less than 28%, peak is located by force than being not less than 20% at 8.374 ± 0.2 ° in 2 θ angles, peak is located by force than being not less than 20% at 11.705 ± 0.2 ° in 2 θ angles, 2 θ angles are at peak, 12.306 ± 0.2 ° of places by force than being not less than 21%, and peak is located by force than being not less than 25% at 17.858 ± 0.2 ° in 2 θ angles.
Its infrared absorption spectrum of Ivacaftor new crystal D of the present invention has characteristic absorbance at 3332cm-1,3113cm-1,2954cm-1,1649cm-1,1526cm-1,1475cm-1,1400cm-1,1286cm-1,1191cm-1,766cm-1 place.
Ivacaftor new crystal D DSC of the present invention characterizes, and its fusing point is 288.85 DEG C and 311.54 DEG C.
Ivacaftor new crystal D of the present invention is measured by TGA, and crystal formation has the loss of 1.28% between 90-150 DEG C, provides ~ the water of 0.28eq.
The new crystal D of above-mentioned Ivacaftor is realized by following steps:
Be scattered in by Ivacaftor in recrystallisation solvent, heating makes dissolution of solid, Slow cooling crystallization, filters, dry, obtains the crystallization of Ivacaftor.
In above-mentioned preparation process, described recrystallisation solvent is the mixing solutions of acetonitrile and water, and the volume ratio of described acetonitrile, water and Ivacaftor is 6 ~ 20:1 ~ 4:1, preferably 9 ~ 11:1 ~ 2:1;
Described heating for dissolving temperature be 40 DEG C to reflux temperature, be preferably 80 DEG C;
Described cooling crystallization temperature is-15 DEG C ~ 30 DEG C, is preferably-10 DEG C ~ 25 DEG C;
Described cooling time is more than 3 hours, is preferably 12 ~ 24 hours;
Described drying mode and temperature are undertaken by existing common process, and usually adopt vacuum drying mode, temperature is preferably 30 ~ 60 DEG C; Preferably 6 ~ 24 hours time of drying.
After the solids dissolve, activated carbon decolorizing can be added, then filtered while hot to decolour, then by filtrate Slow cooling crystallization.The consumption of described gac is generally 5% ~ 10% of Ivacaftor consumption, and bleaching time is generally 10-30 minute.
The stability experiment of crystallization proves that the crystal formation D crystallization purity that the present invention obtains is high, good stability, is applicable to storing and using as bulk drug.
Compared with prior art, new crystal D that the invention provides a kind of Ivacaftor and preparation method thereof, advantage is:
1. crystalline technological operation is simple, and product yield is high, and production cost is low, environmental friendliness, can suitability for industrialized production, has extremely strong practicality;
2. the Crystal type obtained is even, specific volume is little, be easy to packing;
3. the crystallization purity obtained is high, good stability, is applicable to storing and using as bulk drug.
Accompanying drawing explanation
Fig. 1 is the X-ray diffracting spectrum of Ivacaftor new crystal D of the present invention;
Fig. 2 is the infrared spectra collection of illustrative plates of Ivacaftor new crystal D of the present invention;
Fig. 3 is that the differential scanning calorimetry (DSC) of Ivacaftor new crystal D of the present invention analyzes collection of illustrative plates, and its DSC melting transition is at 288.85 DEG C and 311.54 DEG C.
Fig. 4 is that the heat of Ivacaftor new crystal D of the present invention loses heavily (TGA) and analyzes collection of illustrative plates.
Fig. 5 is the X-ray diffracting spectrum of Ivacaftor new crystal D of the present invention;
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20 ~ 35 DEG C.Unless otherwise indicated, the not purified direct use of described reagent.The equal available from commercial supplier of all solvents, such as aldrich (Aldrich), and not treatedly just can to use.
X-PRD spectrum gathers on Bruker D8Advance diffractometer (copper target,
).
DSC spectrum collects on TA Instruments DSC Q2000 instrument.
TGA spectrum collects on TA Instruments TGA Q500 instrument.
FT-IR spectrum collects on Nicolet is5 spectrograph.
Embodiment 1
50g Ivacaftor is scattered in 450mL acetonitrile and 50mL water, and temperature rising reflux (82 DEG C), solid is entirely molten, stirred under reflux temperature 30min.Temperature fall to room temperature (20 DEG C), filter, filter cake with acetonitrile wash once, collect solid, solid vacuum-drying 12 hours, obtains Ivacaftor crystallization 43.5g, yield 87%, purity 99.42%.This crystallization X-ray diffraction analysis, infrared spectrum characterization, dsc analysis, TGA analyze, and as accompanying drawing 1,2,3,4, this crystal formation are defined as form D.
Embodiment 2
100g Ivacaftor is scattered in 1000mL acetonitrile and 100mL water, is slowly warming up to 60 DEG C, and solid is entirely molten, add 5g activated carbon decolorizing 30min, filtered while hot removing gac, filtrate is warming up to backflow, stirred under reflux temperature 30min, Temperature fall crystallization, is cooled to 0 DEG C, stir 30min, filter, filter cake with acetonitrile wash once, collect filter cake vacuum-drying 12 hours, obtain Ivacaftor crystallization 84g, yield 84%, purity 99.53%.This crystallization X-ray diffraction is analyzed as accompanying drawing 5.
Embodiment 3
The crystallization of Ivacaftor embodiment 1 and embodiment 2 obtained is laid on crystallizing dish, temperature 40 DEG C ± 2 DEG C, places 3 months under the condition of relative humidity 75% ± 5%, investigates the stability of crystallization, the results are shown in following table:
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (8)
1. a new crystal D of Ivacaftor, is characterized in that: the powder X-ray diffraction figure of this crystal formation represents to have characteristic peak at 4.082 ± 0.2 °, 6.135 ± 0.2 °, 7.563 ± 0.2 °, 8.374 ± 0.2 °, 9.184 ± 0.2 °, 11.705 ± 0.2 °, 12.306 ± 0.2 °, 17.858 ± 0.2 °, 18.759 ± 0.2 °, 20.92 ± 0.2 ° places with 2 θ angles.
2. the new crystal D of a kind of Ivacaftor according to claim 1, it is characterized in that: in the powder x-ray diffraction figure of this crystal, 2 θ angles at the peaks at 4.082 ± 0.2 ° of places by force than being 100%, 2 θ angles 7.563 ± 0.2 ° place peaks by force than being not less than 28%, peak is located by force than being not less than 20% at 8.374 ± 0.2 ° in 2 θ angles, peak is located by force than being not less than 20% at 11.705 ± 0.2 ° in 2 θ angles, 2 θ angles are at peak, 12.306 ± 0.2 ° of places by force than being not less than 21%, and peak is located by force than being not less than 25% at 17.858 ± 0.2 ° in 2 θ angles.
3. the new crystal D of a kind of Ivacaftor according to claim 1, is characterized in that: the infrared absorption spectrum of this crystal formation has charateristic avsorption band at 3332cm-1,3113cm-1,2954cm-1,1649cm-1,1526cm-1,1475cm-1,1400cm-1,1286cm-1,1191cm-1,766cm-1 place.
4. the new crystal D of a kind of Ivacaftor according to claim 1, be is characterized in that: characterized by DSC trace, and described DSC trace is included in the endotherm(ic)peak at 288.85 ± 2 DEG C and 311.54 ± 2 DEG C places.
5. for the preparation of the preparation method of the Ivacaftor new crystal D according to any one of claim 1-4, it is characterized in that, comprise the following steps: Ivacaftor is scattered in the mixing solutions of acetonitrile and water, be heated to make dissolution of solid, Slow cooling crystallization, filter, dry, obtain the crystallization of Ivacaftor.
6. the preparation method of Ivacaftor new crystal D as claimed in claim 5, it is characterized in that, the volume ratio of described acetonitrile, water and Ivacaftor is 6 ~ 20:1 ~ 4:1, described heating for dissolving temperature be 40 DEG C to reflux temperature, described cooling crystallization temperature is-15 DEG C ~ 30 DEG C, described cooling time is more than 3 hours, and described drying mode is vacuum-drying.
7. the preparation method of the new crystal D of Ivacaftor as claimed in claim 6, it is characterized in that, the volume ratio of described acetonitrile, water and Ivacaftor is 9 ~ 11:1 ~ 2:1, and described heating for dissolving temperature is 80 DEG C, and described cooling crystallization temperature is-10 DEG C ~ 25 DEG C; Described cooling time is 12 ~ 24 hours, and the temperature of described vacuum drying mode is 30 ~ 60 DEG C; Time of drying is 6 ~ 24 hours.
8. the preparation method of the new crystal D of the Ivacaftor as described in claim 5-7, is characterized in that, also comprises the step of decolouring.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510126289.6A CN104725314A (en) | 2015-03-23 | 2015-03-23 | New crystal form of Ivacaftor and preparation method thereof |
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| CN201510126289.6A CN104725314A (en) | 2015-03-23 | 2015-03-23 | New crystal form of Ivacaftor and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237414A (en) * | 2015-09-30 | 2016-01-13 | 浙江永宁药业股份有限公司 | Ivacaftor intermediate, and preparation method and use thereof |
| US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| WO2017187336A1 (en) | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2017187340A1 (en) | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
| US10206915B2 (en) | 2016-04-25 | 2019-02-19 | Druggability Technologies Ip Holdco Limited | Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| US10383865B2 (en) | 2016-04-25 | 2019-08-20 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
| WO2022086434A1 (en) | 2020-10-22 | 2022-04-28 | Scinopharm Taiwan, Ltd. | A novel crystalline form of ivacaftor and a process for preparing the same |
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| CN101384172A (en) * | 2005-12-28 | 2009-03-11 | 沃泰克斯药物股份有限公司 | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| WO2013067410A1 (en) * | 2011-11-02 | 2013-05-10 | Vertex Pharmaceuticals Incorporated | Use of (n- [2, 4 -bis (1, 1 -dimethylethyl) - 5 - hydroxyphenyl] - 1, 4 - dihydro - 4 - oxoquinoline - 3 - ca rboxamide) for treating cftr mediated diseases |
| CN103180298A (en) * | 2010-03-19 | 2013-06-26 | 沃泰克斯药物股份有限公司 | Solid form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydr o-4-oxoquinoline-3-carboxamide |
| WO2014118805A1 (en) * | 2013-01-31 | 2014-08-07 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for the preparation of ivacaftor and solvates thereof |
-
2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101384172A (en) * | 2005-12-28 | 2009-03-11 | 沃泰克斯药物股份有限公司 | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| CN103180298A (en) * | 2010-03-19 | 2013-06-26 | 沃泰克斯药物股份有限公司 | Solid form of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydr o-4-oxoquinoline-3-carboxamide |
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| WO2014118805A1 (en) * | 2013-01-31 | 2014-08-07 | Glenmark Pharmaceuticals Limited; Glenmark Generics Limited | Process for the preparation of ivacaftor and solvates thereof |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| CN105237414A (en) * | 2015-09-30 | 2016-01-13 | 浙江永宁药业股份有限公司 | Ivacaftor intermediate, and preparation method and use thereof |
| CN105237414B (en) * | 2015-09-30 | 2017-03-22 | 浙江永宁药业股份有限公司 | Ivacaftor intermediate, and preparation method and use thereof |
| WO2017187336A1 (en) | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2017187340A1 (en) | 2016-04-25 | 2017-11-02 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
| US10206915B2 (en) | 2016-04-25 | 2019-02-19 | Druggability Technologies Ip Holdco Limited | Complexes of Ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| US10383865B2 (en) | 2016-04-25 | 2019-08-20 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of Ivacaftor and Lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
| US10675277B2 (en) | 2016-04-25 | 2020-06-09 | Nangenex Nanotechnology Incorporated | Complexes of ivacaftor and its salts and derivatives, process for the preparation thereof and pharmaceutical compositions containing them |
| WO2022086434A1 (en) | 2020-10-22 | 2022-04-28 | Scinopharm Taiwan, Ltd. | A novel crystalline form of ivacaftor and a process for preparing the same |
| US11384054B2 (en) | 2020-10-22 | 2022-07-12 | Scinopharm Taiwan, Ltd. | Crystalline form of ivacaftor and a process for preparing the same |
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