CN101962387A - Clopidogrel bisulfate in novel crystalline form and preparation method thereof - Google Patents
Clopidogrel bisulfate in novel crystalline form and preparation method thereof Download PDFInfo
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Abstract
The invention relates to clopidogrel bisulfate in a novel III type crystalline form and a preparation method thereof. III type crystals are non-solvent crystals; powder diffraction spectrum of X rays radiated by Cu-Ka and represented by a diffraction angle has one or more peaks at 9.1, 10.8, 11.2, 11.4 and the like; and the differential scanning calorimetric endothermic transition temperature of the clopidogrel bisulfate in the novel III type crystalline form is 226.1+/-2 DEG C. The invention also provides the preparation method for the high-purity crystalline clopidogrel bisulfate. The clopidogrel bisulfate in the III type crystalline form provided by the invention has higher thermal stability to further achieve higher storability, vaster market prospect and higher popularization value.
Description
Technical field
The present invention relates to antithrombotic reagent SR-25990C (Clopidogrel bisulfate) i.e. (2S)-2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) a kind of new crystal habit and preparation method thereof of methyl acetate hydrosulfate.
Background technology
SR-25990C is a kind of anti-platelet aggregation medicine, be used for the treatment of acute thrombotic cardiovascular and cerebrovascular diseases and operate on surgical procedure, be applicable to the apoplexy of outbreak in the recent period, myocardial infarction and the patient who makes a definite diagnosis peripheral arterial disease, this medicine can reduce the generation of atherosclerotic incident, reduce myocardial infarction, apoplexy and vascular mortality risk.
The chemistry of SR-25990C is by name: (2S)-2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) methyl acetate hydrosulfate, its structural formula is as follows:
This medicine is narrated in European patent EP 281459 to some extent, and the synthetic method of this part patent application protection is the preparation method who is known as I type crystalline SR-25990C.1999, St. Sanofi-Synthelabo Corporation found second kind of crystal habit (being known as the crystallization of II type) of SR-25990C again, and had applied for patent, Granted publication CN1128805 in China.Four kinds of solvation crystal habits that in March, 2007 China patent CN1923835 discloses SR-25990C (are the solvate that SR-25990C forms with 1-butanols, 2-butanols, 1-propyl alcohol, 2-propyl alcohol respectively, in this application, be called as III, IV, V, VI type respectively,) and amorphous, the application people is an Israel Teva Pharmaceutical Industries Ltd.So-called solvation crystallization is promptly in crystallisation process, and because of the crystallization that the adding of solvent molecule makes the crystalline lattice change and obtain, it is not the crystallization of one matter, but crystalline mixture.Find that at present also there is the third non-solvent crystal habit in SR-25990C, new crystal habit promptly provided by the present invention, this crystal habit are called as the crystallization of III type in this application.
Summary of the invention
Main purpose of the present invention is that III type crystalline SR-25990C is provided.
The objective of the invention is by a kind of new crystal habit is provided---III type crystalline SR-25990C reaches.
The crystallization of III type is a kind of non-solvent crystallization, it is represented with diffraction angle (2 θ), use the alpha-emitting X-ray powder diffraction of Cu-K (being called for short " XRD ") spectrum 9.1,10.8,11.2,11.4,13.6,14.7,14.9,15.7,17.8,18.2,18.7,19.3,19.7,20.1,20.8,21.9,22.8,23.2,24.1,24.4,24.9,25.3,25.9,26.4,26.8,27.2,28.6,28.9,29.5,29.9,30.1,30.7,31.5,31.7,32.4,32.7,33.9,34.4,35.0,36.0 one or more (with any combination) peak is arranged, specifically sees accompanying drawing 1.
III type crystalline DSC endothermic transition is seen Fig. 2 about 226.1 ± 2 ℃ (with heat-up rates of 10 ℃/minute).
3418,2989,2953,2704,2593,1754,1631,1434,1352,1322,1296,1222,1163,1065cm it is as follows that the infrared extinction of III type crystalline spectrum (see figure 3) is received feature:
-1
The present invention also provides the preparation method of the SR-25990C of high-purity crystallized attitude.
Following several preparation method can be arranged:
The one, clopidogrel free alkali is dissolved in the crystallization solvent, slowly drip the vitriol oil being no more than under 40 ℃ the condition, the consumption mol ratio of the clopidogrel free alkali and the 98% mass concentration vitriol oil is 10: 9.5 to 10: 11, stirred crystallization.
The 2nd, with the amorphous heating for dissolving of the solvate of other crystal formation of SR-25990C or SR-25990C or SR-25990C in the crystallization solvent, slowly be cooled under the condition that is no more than 40 ℃ then and stir, carry out the recrystallization preparation.
The 3rd, clopidogrel free alkali is dissolved in the intensive polar solvent, slowly drip the 98% mass concentration vitriol oil, the consumption mol ratio of the clopidogrel free alkali and the 98% mass concentration vitriol oil is 10: 9.5 to 10: 11, add the above weak polar solvent of 3 times of volumes of above-mentioned reaction solution then, be no more than stirred crystallization under 40 ℃ the condition.
The 4th, with the amorphous heating for dissolving of the solvate of other crystal formation of SR-25990C or SR-25990C or SR-25990C in intensive polar solvent, add the above weak polar solvent of 3 times of volumes of above-mentioned solution then, slowly be cooled to stirred crystallization under the condition that is no more than 40 ℃.
The crystallization solvent that the present invention adopts is the mixture of intensive polar solvent, weak polar solvent and intensive polar solvent and weak polar solvent; Or their arbitrary composition and single intensive polar solvent or their arbitrary combination are with can be miscible single or mix the mixture of weak polar solvent.
It is the crystallization solvent that the present invention adopts the mixture of intensive polar solvent and intensive polar solvent and weak polar solvent, can effectively go out the bigger impurity of depolarization, as o-chlorobenzene glycine, O-chlorobenzene glycine methyl ester, clopidogrel hydrolyzate etc.
The present invention has also adopted elder generation to dissolve with intensive polar solvent, and the mode that extrude with weak polar solvent the back is carried out crystallization.
Above-mentioned intensive polar solvent comprises alcohol, water, tetrahydrofuran (THF), second cyanogen, N, dinethylformamide, N,N-dimethylacetamide etc. or their arbitrary composition.
Above-mentioned weak polar solvent comprises ketone, ester, ether, alkane, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene, dioxane, sherwood oil etc. or their arbitrary composition.
Alcohol in the above-mentioned recrystallisation solvent is meant the alkyl alcohol that contains 1-8 carbon atom, and these alkyl comprise straight chain, branch-like and cyclic; This alcohol comprises primary, secondary, the tertiary alcohol; For example methyl alcohol, ethanol, Virahol etc.
Ketone in the above-mentioned weak polar solvent has R
1C (=O) R
2The ketone of structure.Alkyl R
1With alkyl R
2Be meant the straight chain, side chain or the cyclic alkyl that contain 1-6 carbon atom, R
1And R
2Can be identical, also can be different.For example acetone, butanone, positive pentanone, isoamyl ketone etc.
Ester in the above-mentioned weak polar solvent has R
1C (=O) OR
2The ester of structure.Alkyl R
1With alkyl R
2Be meant the straight chain, side chain or the cyclic alkyl that contain 1-6 carbon atom, R
1And R
2Can be identical, also can be different.For example methyl acetate, ethyl acetate, butylacetate etc.
Ether in the above-mentioned weak polar solvent has R
1-O-R
2Structure.Alkyl R
1With alkyl R
2Be meant the straight chain, side chain or the cyclic alkyl that contain 1-6 carbon atom, can be identical, also can be different.For example ether, propyl ether, isopropyl ether etc.
Alkane in the above-mentioned weak polar solvent is straight chain, side chain or the cyclic alkane that 3-16 carbon atom arranged.For example normal hexane, hexanaphthene etc.
III type crystalline SR-25990C disclosed by the invention has better thermostability, thereby has better storage performance, thereby has better application prospect and promotional value.
Description of drawings
Fig. 1 III type crystalline X-ray powder diffraction (being called for short " XRD ") collection of illustrative plates.
Fig. 2 III type crystalline differential scanning calorimetric analysis (being called for short " DSC ") collection of illustrative plates.
Fig. 3 III type crystalline infrared absorpting light spectra (being called for short " IR ").
The crystallization of Fig. 4 III type contrasts collection of illustrative plates with I type, II type crystalline XRD, and wherein ordinate zou is followed successively by I type, II type, III type crystalline collection of illustrative plates from the bottom up.
Embodiment
Below in conjunction with embodiment the present invention is further described in detail, but be not limitation of the invention.In addition, except as otherwise noted, in this manual, temperature be meant centigradetemperature (℃), room temperature is meant 10-25 ℃.
The sign of the crystal habit of experimental example one SR-25990C
The present invention adopts several method (normally use XRD, DSC differential scanning calorimetric analysis and TGA thermogravimetric analysis figure, can also be assisted card with the fourier-transform infrared absorption spectrum simultaneously) that III type crystalline feature is characterized.The operator generally uses XRD to characterize that crystalline is formed or it is identified (referring to two ones of Pharmacopoeia of the People's Republic of China versions in 2005, appendix IX F method, 64 pages of appendix, appendix VIII Q method, 57 pages of appendix, appendix IV C method, 23 pages of appendix, Chemical Industry Press).The diffractogram that is obtained by crystalline compounds is distinctive often for a given crystal habit, though weak or very weak diffraction peak may always not occur in the same diffractogram that the crystallization by continuous lot number obtains.Especially in sample, have under the situation of other crystal habit of significant quantity.The relative intensity of bands of a spectrum [especially in low angle X ray incident value (2 θ)] may change because of the advantage orientation effect that is produced by the difference of for example crystal habit, particle diameter and other condition determination.Therefore, the relative intensity of diffraction peak be not at last at crystal habit be distinctive.On the contrary, more it should be noted the relative position at peak rather than their amplitude, to determine whether the SR-25990C crystallization is the crystallization of described III type herein.Each XRD peak in the different samples is generally in about 0.3-1 (2 θ) degree that is broad peak.The XRD peak of broad can be made up of the two or more peaks that abut against together.For isolated spike, in the successive XRD analysis, in about 0.1 (2 θ) degree, find the peak usually.Suppose in the successive XRD analysis XRD spectrum with identical a kind of compound of Instrument measuring, then the difference of XRD peak position mainly is because in the specimen preparation process or due to the difference of sample self purity.When we identify one independently during the XRD spike in a given position (for example about 11.2), this means that this peak is 11.2 ± 0.1.When we when the given position that is positioned at given 2 θ values identifies an XRD broad peak, this means that this peak is in this 2 θ value ± 0.3.
Be to be noted that in the present invention, need not to rely on observed whole bands of a spectrum in the highly purified control sample; Even bands of a spectrum may be features to given SR-25990C crystal habit also, as 11.2,15.7,20.8 for III type crystal habit.Evaluation should concentrate on the position and the overall collection of illustrative plates of bands of a spectrum, especially select various crystal habits unique bands of a spectrum.
Can optionally be used in addition identifies that the diagnostic techniques of crystalline clopidogrel hydrosulfate comprises differential scanning calorimetry (DSC), fusing point test and infrared absorption spectrometry (IR).DSC measures when crystallization and changes owing to its crystalline structure or the crystal fusion absorbs or thermal transition temperature during rejected heat.In successive was analyzed, thermal transition temperature was typically within about 2.0 ℃.When saying a compound, we have the DSC peak of a set-point within ± 2 ℃.DSC provides a kind of alternative method of distinguishing different SR-25990C crystal habits.Different crystal habits can be discerned according to different transition temperature characteristics (at least partially).IR measures the infrared Absorption have the particular chemical key relevant with the group that vibrates corresponding to light in the molecule to cause.DSC and/or IR can provide therefrom and can be used for describing SR-25990C crystalline physics and chemistry information.
The XRD figure spectrum of III type crystalline clopidogrel hydrosulfate of the present invention has one or more (with any combination) peak about 9.1,10.8,11.2,11.4,14.7,14.9,15.7,18.2,18.7,20.8,21.9,22.8,24.1,24.4,24.9 usually.Typically, at about 11.2 and/or 15.7 and/or 20.8 XRD peak or usually (1) this peak add peak that one or several is other or (2) add at about 11.2 and/or 15.7 and/or 20.8 peak one or several other peak add differential scanning calorimetry (DSC) data or fusing point data or TGA thermogravimetric analysis collection of illustrative plates be enough to III type crystalline clopidogrel hydrosulfate and I, the crystallization of II type and other solvation crystallizations make a distinction or to the III type crystallization self identify.Fig. 1 is the X-ray diffractogram of typical III type crystalline clopidogrel hydrosulfate.
III type crystalline clopidogrel hydrosulfate is anhydrous, the water that contains seldom or can not survey.Usually, the crystallization of this form generally contains the water less than about 1% (typically less than about 0.5%, usually less than about 0.2%).This crystal habit does not contain the crystallization solvent, that is, contained crystallization solvent is typically less than about 1%, less than about 0.5%, does not contain the solvent molecule that is bound by lattice usually, that is to say not to be solvation crystallization or solvate.
The crystallization of III type has DSC endothermic transition (referring to Fig. 2) at about 226.1 ℃, and has basically IR spectrum as shown in Figure 3.
The preparation method of embodiment two III type crystalline clopidogrel hydrosulfates
Method one is dissolved in the crystallization solvent with clopidogrel free alkali, and (40 ℃ to 20 ℃ are typically-5 ℃ to 0 ℃) slowly drips and wait the mole vitriol oil, stirred crystallization under the proper temperature condition.
Method two is dissolved in 1 or 2 type crystallizations of SR-25990C heating (50 ℃-80 ℃ are typically 60 ℃-70 ℃) in the crystallization solvent, and cooling and stirring (40 ℃ to 20 ℃ are typically-10 ℃ to 0 ℃) is slowly carried out recrystallization and prepared then.
Method three is dissolved in clopidogrel free alkali in the intensive polar solvent, as methyl alcohol, ethanol, second cyanogen etc., (40 ℃ to 20 ℃ are typically-5 ℃ to 0 ℃) slowly drips and waits the mole vitriol oil under the proper temperature condition, after dropwising, slowly add the weak polar solvent stirred crystallization again.
Method four heats (50 ℃-80 ℃ with 1 or 2 type crystallizations of SR-25990C, be typically 60 ℃-70 ℃) be dissolved in the minimum single or mixing intensive polar solvent, as methyl alcohol, ethanol, second cyanogen etc., add weak polar solvent again after dissolving finishes and cool off (40 ℃ to 20 ℃ are typically-10 ℃ to 0 ℃) stirred crystallization gradually.
The purity of the III type crystalline clopidogrel hydrosulfate that above-mentioned four kinds of methods obtain at least greater than 98.5% (W: W), usually more than 99.0%; Simultaneously, the crystallization of III type is simple and easy to do in preparation, is fit to large-scale industrialization production; The crystallization of III type has thermostability and flowability preferably, is easy to be mixed with therapeutical agent; Adopt the adjustable crystallization solvent of polarity to carry out crystallization, can effectively remove the bigger impurity of polarity that is difficult to remove with additive method.
The concrete preparation method 1 of embodiment
With 100g (0.31mol, chromatographic purity is 90.45%) clopidogrel free alkali is dissolved in 500ml ethanol, be cooled to-5 ℃ to 0 ℃, slowly drip 32g (0.327mol) the 98% mass concentration vitriol oil, continue at-5 ℃ to 0 ℃ stirred crystallization 12 hours, filter, the acetone top is washed, 45 ℃ of vacuum-drying 4 hours promptly gets III type crystallinity white powder 112g (chromatographic purity is 98.98%).
The concrete preparation method 2 of embodiment
With 116g (0.276mol, chromatographic purity is 94.45%) 1 type crystallization of SR-25990C adds 1200ml ethanol, be heated to 70 ℃ and stir 40min, after treating that solution becomes is clear, be cooled to-5 ℃ to 0 ℃ stirred crystallization 24 hours, and filtered, the acetone top is washed, 45 ℃ of vacuum-drying 4 hours, III type crystallinity white powder 95g (chromatographic purity is 99.21%).
The concrete preparation method 3 of embodiment
With 100g (0.31mol, chromatographic purity is 90.45%) clopidogrel free alkali is dissolved in 500ml ethanol and the 50ml water, be cooled to-5 ℃ to 0 ℃, slowly drip 32g (0.327mol) vitriol oil, dropwise the back and add 300ml acetone, continue at-5 ℃ to 0 ℃ stirred crystallization 5 hours, filter, acetone top is washed, and 45 ℃ of vacuum-drying 4 hours promptly gets III type crystallinity white powder 115g (chromatographic purity is 99.55%).
The concrete preparation method 4 of embodiment
With 116g (0.276mol, chromatographic purity is 94.45%) 1 type crystallization of SR-25990C adds 500ml ethanol, be heated to 70 ℃ and stir 40min, under agitation slowly add entry and make solution becomes clear, add entry 20ml altogether, added 400ml acetone stirred crystallization 5 hours after being cooled to-5 ℃ to 0 ℃, filter, acetone top is washed, 45 ℃ of vacuum-drying 4 hours, III type crystallinity white powder 101.7g (chromatographic purity is 99.71%).
The concrete preparation method 5 of embodiment
With 116g (0.276mol, chromatographic purity is 96.37%) 2 type crystallizations of SR-25990C add 1200ml ethanol, be heated to 70 ℃ and stir 40min, after treating that solution becomes is clear, be cooled to-5 ℃ to 0 ℃ stirred crystallization 24 hours, and filtered, the acetone top is washed, 45 ℃ of vacuum-drying 4 hours, III type crystallinity white powder 96.7g (chromatographic purity is 99.28%).
The concrete preparation method 6 of embodiment
With 116g (0.276mol, chromatographic purity is 96.37%) 1 type crystallization of SR-25990C adds 500ml ethanol, be heated to 70 ℃ and stir 40min, under agitation slowly add entry and make solution becomes clear, add entry 20ml altogether, added 400ml acetone stirred crystallization 5 hours after being cooled to-5 ℃ to 0 ℃, filter, acetone top is washed, 45 ℃ of vacuum-drying 4 hours, III type crystallinity white powder 104.2g (chromatographic purity is 99.78%).
Claims (9)
1. the SR-25990C of a novel crystalline form attitude, it is characterized in that: the SR-25990C of described novel crystalline form attitude is used Cu-K α radiation, with the X-ray powder diffraction spectrum of diffraction angle (2 θ) expression 9.1 ± 0.1,10.8 ± 0.1,11.2 ± 0.1,11.4 ± 0.1,13.6 ± 0.1,14.7 ± 0.1,14.9 ± 0.1,15.7 ± 0.1,17.8 ± 0.1,18.2 ± 0.1,18.7 ± 0.1,19.3 ± 0.1,19.7 ± 0.1,20.1 ± 0.1,20.8 ± 0.1,21.9 ± 0.1,22.8 ± 0.1,23.2 ± 0.1,24.1 ± 0.1,24.4 ± 0.1,24.9 ± 0.1 degree has a plurality of peaks of or any combination.
2. the SR-25990C of novel crystalline form attitude as claimed in claim 1 is characterized in that: the SR-25990C DSC endothermic transition temperature of described novel crystalline form attitude is at 226.1 ± 2 ℃.
3418,2989,2953,2704,2593,1754,1631,1434,1352,1322,1296,1222,1163,1065cm 3. the SR-25990C of novel crystalline form attitude as claimed in claim 1 is characterized in that: the SR-25990C infrared absorption spectrum of described novel crystalline form attitude is characterized as:
-1
4. the preparation method of the SR-25990C of novel crystalline form attitude as claimed in claim 1, it is characterized in that: clopidogrel free alkali is dissolved in the crystallization solvent, slowly drip the 98% mass concentration vitriol oil being no more than under 40 ℃ the condition, the consumption mol ratio of the clopidogrel free alkali and the vitriol oil is 10: 9.5 to 10: 11, stirred crystallization.
5. the preparation method of the SR-25990C of novel crystalline form attitude as claimed in claim 1, it is characterized in that: with the amorphous heating for dissolving of the solvate of other crystal formation of SR-25990C or SR-25990C or SR-25990C in the crystallization solvent, slowly be cooled under the condition that is no more than 40 ℃ then and stir, carry out the recrystallization preparation.
6. the preparation method of the SR-25990C of novel crystalline form attitude as claimed in claim 1, it is characterized in that: clopidogrel free alkali is dissolved in the intensive polar solvent, slowly drip the vitriol oil, the consumption mol ratio of the clopidogrel free alkali and the 98% mass concentration vitriol oil is 10: 9.5 to 10: 11, add the above weak polar solvent of 3 times of volumes of above-mentioned reaction solution then, be no more than stirred crystallization under 40 ℃ the condition.
7. the preparation method of the SR-25990C of novel crystalline form attitude as claimed in claim 1, it is characterized in that: with the amorphous heating for dissolving of the solvate of other crystal formation of SR-25990C or SR-25990C or SR-25990C in intensive polar solvent, add the above weak polar solvent of 3 times of volumes of above-mentioned solution then, slowly be cooled to stirred crystallization under the condition that is no more than 40 ℃.
8. as the preparation method of the SR-25990C of the described novel crystalline form attitude of the arbitrary claim of claim 4 to 7, it is characterized in that: the crystallization solvent comprises the mixture of intensive polar solvent, weak polar solvent and intensive polar solvent and weak polar solvent, wherein said intensive polar solvent comprises alcohol, water, tetrahydrofuran (THF), second cyanogen, N, dinethylformamide, N,N-dimethylacetamide etc. or their arbitrary composition; Weak polar solvent comprises ketone, ester, ether, alkane, methylene dichloride, chloroform, tetracol phenixin, benzene, toluene, dioxane, sherwood oil etc. or their arbitrary composition.
9. the preparation method of the SR-25990C of novel crystalline form attitude as claimed in claim 8 is characterized in that: alcohol is meant the alkyl alcohol that contains 1-8 carbon atom, and these alkyl comprise straight chain, branch-like and cyclic; This alcohol comprises primary, secondary, the tertiary alcohol; Ketone has R
1C (=O) R
2Structure; Ester has R
1C (=O) OR
2Structure; Ether has R
1-O-R
2Structure; Alkane is straight chain, side chain or the cyclic alkane that 3-8 carbon atom arranged; Wherein, R
1And R
2Be meant the straight chain, side chain or the cyclic alkyl that contain 1-6 carbon atom.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817571A (en) * | 2014-12-31 | 2015-08-05 | 天津大学 | Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate |
| CN105061459A (en) * | 2015-07-21 | 2015-11-18 | 深圳信立泰药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I crystal form spherical crystal |
| TWI791916B (en) * | 2018-10-31 | 2023-02-11 | 法商施維雅藥廠 | Novel salt of a bcl-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5576328A (en) * | 1994-01-31 | 1996-11-19 | Elf Sanofi | Method for the secondary prevention of ischemic events |
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
-
2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5576328A (en) * | 1994-01-31 | 1996-11-19 | Elf Sanofi | Method for the secondary prevention of ischemic events |
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817571A (en) * | 2014-12-31 | 2015-08-05 | 天津大学 | Method for preparing I crystal form of spherical clopidogrel hydrogen sulfate |
| CN105061459A (en) * | 2015-07-21 | 2015-11-18 | 深圳信立泰药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I crystal form spherical crystal |
| CN105061459B (en) * | 2015-07-21 | 2016-08-24 | 深圳信立泰药业股份有限公司 | A kind of preparation method of bisulfate clopidogrel I crystal spheroidal crystal |
| WO2016161989A3 (en) * | 2015-07-21 | 2016-12-01 | 深圳信立泰药业股份有限公司 | Preparation method for clopidogrel bisulphate crystalline form i spherical crystals |
| TWI791916B (en) * | 2018-10-31 | 2023-02-11 | 法商施維雅藥廠 | Novel salt of a bcl-2 inhibitor, related crystalline form, method for preparing the same and pharmaceutical compositions containing the same |
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