CN107033137A - A kind of crystal formation of Dasatinib and preparation method thereof - Google Patents
A kind of crystal formation of Dasatinib and preparation method thereof Download PDFInfo
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- CN107033137A CN107033137A CN201610077730.0A CN201610077730A CN107033137A CN 107033137 A CN107033137 A CN 107033137A CN 201610077730 A CN201610077730 A CN 201610077730A CN 107033137 A CN107033137 A CN 107033137A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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 provides a kind of crystal formation of Dasatinib and preparation method thereof.Dasatinib crystal formation provided by the present invention has extremely low initial impurity content, also, can keep excellent stability during active component storage, preparation preparation and formulation storage, and active component is not degraded substantially.
Description
Technical field
The present invention relates to a kind of crystal formation of Dasatinib, belong to medicinal chemistry arts.
Background technology
Entitled N- (the chloro- 6- aminomethyl phenyls of 2-) -2- [[6- [4- (2- ethoxys) -1- the piperazinyls] -2- of Dasatinib chemistry
Methyl -4- pyrimidine radicals] amino] -5- thiazole carboxamides, structural formula is shown in formula I：
Dasatinib can be used for treatment resistance or intolerable chronic myelogenous leukemia (CML) all stadium (chronic
Phase, accelerated period, lymphoid lineage cell CML-BC and myelocyte CML-BC) adult patient.Dasatinib can also be used to treat resistance
Or intolerable Philadelphia chromosome acute lymphoblastic leukemia (Ph+ALL) patient.
The patents such as CN1980909A, CN101891738A, CN102250084A, CN102040596A, WO2009053854
Application discloses a variety of crystal formations of Dasatinib.Because different crystal formations has very big difference in stability, bioavilability
Not, it is therefore necessary to drug molecule progress polymorphic research as much as possible, to ensure to obtain optimal crystal formation.The present invention's
Purpose is a kind of new Dasatinib crystal formation of offer, and its impurity content is low, and with good stability.
The content of the invention
It is surprising that present invention finds a kind of crystal of Dasatinib, the crystal has extremely low initial impurity
Content, also, excellent stability can be kept during active component storage, preparation preparation and formulation storage, activity
Composition is not degraded substantially.
The crystal for the Dasatinib that the present invention is provided, it is characterized in that X-ray powder diffraction spectrum represented with 2 θ 6.7 °,
There is diffraction maximum at 12.4 °, 13.5 °, 18.7 ° and 24.7 °；Typically, X-ray powder diffraction spectrum represented with 2 θ 6.7 °,
There is diffraction maximum at 12.4 °, 13.5 °, 16.9 °, 18.7 °, 21.3 °, 22.1 °, 24.7 ° and 27.9 °.
There is one typical embodiments of the Dasatinib crystal that the present invention is provided X-ray powder as follows to spread out
Penetrate spectrum：
Without limitation, a typical embodiments of the crystal for the Dasatinib that the present invention is provided have as shown in Figure 1
X-ray powder diffraction spectrum.
Without limitation, a typical embodiments of the crystal for the Dasatinib that the present invention is provided have as shown in Figure 2
Means of differential scanning calorimetry (DSC) collection of illustrative plates.Under the heating rate of 10K/ minutes, there is an endothermic peak, the endothermic peak starting point exists
279 DEG C, peak value is 282 DEG C.
Another aspect of the present invention provides a kind of Dasatinib crystalline composition, wherein the crystal of above-mentioned Dasatinib
Account for more than the 50% of crystalline composition weight, preferably more than 80%, more preferably more than 90%, preferably more than 95%.
Another aspect provides a kind of pharmaceutical composition, wherein the above-mentioned Dasatinib comprising therapeutically effective amount
Crystal, or above-mentioned Dasatinib crystalline composition.
Another aspect provides above-mentioned Dasatinib crystal, above-mentioned crystalline composition, or said medicine combination
Thing is preparing the purposes in being used to prevent or treat the medicine of tumour, and preferably it is being prepared for preventing or treating chronic myelognous
Purposes in the medicine of leukaemia or acute lymphoblastic leukemia.
Another aspect provides the side of a kind of crystal for preparing above-mentioned Dasatinib or above-mentioned crystalline composition
Method, the crystal prepared by this method can ensure the high-purity of Dasatinib, and it includes：
(1) Dasatinib crude product is dissolved in DMF, is concentrated into a large amount of solids and separates out, added alcohol reflux stirring, be cooled to room
Temperature, filtering, filter cake is washed with ethanol；
(2) filter cake for obtaining step (1) is dissolved in ethanol and DMF mixed solvent, is heated to reflux 1 hour, is cooled to room
Temperature, filtering, filter cake is washed with ethanol in proper amount, then is heated to reflux 1 hour with ethanol, is cooled to after room temperature and is filtered, dries.
In some typical embodiments, the ratio of Dasatinib and DMF in step (1) is 1mg：3ml~7ml；
It is preferred that 1mg：5ml.
In some typical embodiments, the in the mixed solvent of step (2), the volume ratio of DMF and ethanol is 1：5~
15；It is preferred that 1：10.
In some typical embodiments, the drying condition in step (2) is 90~115 DEG C of dryings, preferably at 105 DEG C
Under be dried under reduced pressure.
In the present invention, the X-ray powder diffraction spectrum of sample is determined under the following conditions：Instrument：Bruker D2 X are penetrated
Line diffractometer；Test condition：30kv 10mA；Slit：0.6mm/3mm/0.8mm；Target type：Cu；Angular range：5-40°；Step-length
0.1s/0.02°。
In the present invention, DSC spectrum are determined under the following conditions：Instrument：The type differential thermal analyzers of Mettler 1；Temperature range：
30-270℃；Heating rate：10℃/min.
In the present invention, the preparation method that the crude product of Dasatinib is referred in CN200580011916.6 is prepared.
In the present invention, in addition to specifying, used ethanol is absolute ethyl alcohol.
In the present invention, in addition to specifying, DMF refers to DMF.
In the present invention, in addition to specifying, room temperature refers to 20 DEG C to 25 DEG C.
In the present invention, impurity A has structure shown below：
It should be noted that in X-ray powder diffraction spectrum, the diffraction spectrogram obtained by crystalline compounds is for spy
Fixed crystal formation is often characteristic, wherein the relative intensity of bands of a spectrum (especially in low angle) may because of crystal condition,
The difference of particle diameter and other condition determinations and the advantage orientation effect that produces and change.Therefore, the relative intensity of diffraction maximum is to institute
For crystal formation be not characteristic, when judging whether identical with known crystal formation, it should be noted that the relative position at peak
Put rather than their relative intensity.In addition, for any given crystal formation, the position at peak there may be slight errors, this
It is also known in crystallography art.For example, due to analysis sample when temperature change, sample movement or instrument demarcation
Deng the position at peak can be moved, and the evaluated error of 2 θ values is about ± 0.2 ° sometimes.Therefore, should it is determined that during every kind of crystalline texture
This takes this error into account.Peak position generally is represented away from d with 2 θ angles or crystal face in XRD spectrum, between the two with simple
Conversion relation：D=λ/2sin θ, wherein d represent crystal face away from λ represents the wavelength of incident X-rays, and θ is the angle of diffraction.For of the same race
The crystal formation of the same race of compound, the peak position of its XRD spectrums has similitude on the whole, and relative intensity error may be larger.Should also
, it is noted that in the identification of mixture, because the factors such as content decline can cause the missing of part diffracted ray, now, without
The whole bands of a spectrum observed in high-purity sample are relied on, or even a bands of a spectrum may also be characteristic to given crystal.
DSC is determined when crystal is because its crystal structure changes or crystal melt and transformation temperature when absorbing or discharge heat
Degree.For the crystal formation of the same race of same compound, in continuous analysis, thermal transition temperature and fusing point error are typical at about 5 DEG C
Within, generally within about 3 DEG C, when we say that a compound has a given DSC peaks or fusing point, this refers to the DSC
Peak or fusing point ± 5 DEG C.DSC provides a kind of householder method for distinguishing different crystal forms.Different crystal habits can be different according to it
Transition temperature feature and recognized.It is to be noted that for mixture, its DSC peak or fusing point may be bigger
In the range of change.Further, since with decomposition during material melts, therefore fusion temperature is related to heating rate.
Brief description of the drawings
Fig. 1：Dasatinib crystal X-ray powder diffraction spectrum；
Fig. 2：Dasatinib crystal Differential Scanning Calorimetry.
Embodiment
The Dasatinib of embodiment 1 it is refined
1.68kg Dasatinib crude products are added in 30L reaction bulbs, 5.1L DMF are dissolved by heating, filtering is concentrated into a large amount of
Solid is separated out, and is added 16.8L alcohol refluxs stirring 1h, is cooled to room temperature, filters, filter cake is washed with ethanol.
It is to add above-mentioned filter cake, 25.2L ethanol, 1.68L DMF in 30L reaction bulbs, is heated to reflux under stirring 1 hour,
Room temperature is cooled to, is filtered, filter cake washs with ethanol, with 16.8L alcohol heat reflux 1 hour, is cooled to after room temperature and filters, 105 DEG C
It is dried under reduced pressure 12 hours, 1.57kg white crystals of weighing to obtain, yield 93.5%.
The Dasatinib of embodiment 2 it is refined
1.68kg Dasatinib crude products are added in 30L reaction bulbs, 8.4L DMF are dissolved by heating, filtering is concentrated into a large amount of
Solid is separated out, and is added 16.8L alcohol refluxs stirring 1h, is cooled to room temperature, filters, filter cake is washed with ethanol.
It is in 30L reaction bulbs to add above-mentioned filter cake, 16.8L ethanol, 1.68L DMF, is heated to reflux 1 under stirring small
When, room temperature is cooled to, is filtered, filter cake is washed with ethanol, with 16.8L alcohol heat reflux 1hr, is cooled to after room temperature and filters, 105 DEG C
It is dried under reduced pressure 12 hours, 1.60kg white crystals of weighing to obtain, yield 95.2%.
The Dasatinib of embodiment 3 it is refined
1.68kg Dasatinib crude products are added in 30L reaction bulbs, 11.8L DMF are dissolved by heating, filtering is concentrated into big
Measure solid to separate out, add 16.8L alcohol refluxs stirring 1h, be cooled to room temperature, filter, filter cake is washed with ethanol.
It is in 30L reaction bulbs to add above-mentioned filter cake, 8.4L ethanol, 1.68L DMF, is heated to reflux 1 under stirring small
When, room temperature is cooled to, is filtered, filter cake washs with ethanol, with 16.8L alcohol heat reflux 1 hour, is cooled to after room temperature and filters, 105
DEG C it is dried under reduced pressure 12 hours, weigh to obtain 1.52kg white crystals, yield 90.5%.
The stability experiment of embodiment 4
The Dasatinib crystal that Example 2 is prepared, with reference to the C bulk drugs of two annex of Chinese Pharmacopoeia Ⅺ Ⅹ and medicine
The method of preparation stability test direction principle investigates the stability of Dasatinib crystal, specific as follows：
As a result it is as follows：
Exposure experiments to light result
Hot test result
High humidity result of the test
Accelerated test result
Long-term test results
Claims (9)
1. a kind of crystal of Dasatinib, it is characterized in that X-ray powder diffraction spectrum represented with 2 θ 6.7 °, 12.4 °,
There is diffraction maximum at 13.5 °, 18.7 ° and 24.7 °；Typically, X-ray powder diffraction spectrum represented with 2 θ 6.7 °, 12.4 °,
There is diffraction maximum at 13.5 °, 16.9 °, 18.7 °, 21.3 °, 22.1 °, 24.7 ° and 27.9 °.
2. the crystal described in claim 1, it is characterised in that with X-ray powder diffraction spectrum as follows：
。
3. the crystal described in claim 1, it is characterised in that with X-ray powder diffraction spectrum as shown in Figure 1.
4. the crystal described in claim 1, it is characterised in that with means of differential scanning calorimetry (DSC) collection of illustrative plates as shown in Figure 2,
Under the heating rate of 10K/ minutes, there is the endothermic peak endothermic peak starting point at 279 DEG C, peak value is 282 DEG C.
5. a kind of Dasatinib crystalline composition, the Dasatinib crystal wherein described in any one of Claims 1 to 4 accounts for crystal group
More than the 50% of polymer weight, preferably more than 80%, more preferably more than 90%, preferably more than 95%.
6. a kind of pharmaceutical composition, wherein the Dasatinib crystal described in any one of Claims 1 to 4 comprising therapeutically effective amount
Or the crystalline composition described in claim 5.
7. profit requires the crystalline composition or claim described in Dasatinib crystal or claim 5 described in 1~4 any one
Pharmaceutical composition described in 6 is preparing the purposes in being used to prevent or treat the medicine of tumour, and preferably it is being prepared for preventing
Or purposes in the medicine for the treatment of chronic myelogenous leukemia or acute lymphoblastic leukemia.
8. profit requires the preparation side of the crystalline composition described in Dasatinib crystal or claim 5 described in 1~4 any one
Method：
(1) Dasatinib crude product is dissolved in DMF, is concentrated into a large amount of solids and separates out, added alcohol reflux stirring, be cooled to room temperature,
Filtering, filter cake is washed with ethanol；
(2) filter cake for obtaining step (1) is dissolved in ethanol and DMF mixed solvent, is heated to reflux 1 hour, is cooled to room temperature, mistake
Filter, filter cake is washed with ethanol in proper amount, then is heated to reflux 1 hour with ethanol, is cooled to after room temperature and is filtered, dries.
9. the method described in claim 8, wherein,
The ratio of Dasatinib and DMF in step (1) is 1mg：3ml~7ml；It is preferred that 1mg：5ml；
The volume ratio of the in the mixed solvent of step (2), DMF and ethanol is 1：5~15；It is preferred that 1：10；
Drying condition in step (2) is 90~115 DEG C of dryings, is preferably dried under reduced pressure at 105 DEG C.
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| WO2010067374A2 (en) * | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
| CN102040596A (en) * | 2009-10-10 | 2011-05-04 | 上海希迪制药有限公司 | Dasatinib polymorph and preparation method thereof |
| CN102086195A (en) * | 2011-01-28 | 2011-06-08 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
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| CN104341410A (en) * | 2013-08-09 | 2015-02-11 | 上海科胜药物研发有限公司 | New Dasatinib crystal form and preparation method thereof |
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| CN105106159A (en) * | 2015-09-29 | 2015-12-02 | 青岛华之草医药科技有限公司 | Dasatinib composition tablets for treating leukemia |
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| CN105147687A (en) * | 2015-09-28 | 2015-12-16 | 青岛华之草医药科技有限公司 | Pharmaceutical dasatinib composition capsules for treating leukemia |
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Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010067374A2 (en) * | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
| CN102040596A (en) * | 2009-10-10 | 2011-05-04 | 上海希迪制药有限公司 | Dasatinib polymorph and preparation method thereof |
| CN102086195A (en) * | 2011-01-28 | 2011-06-08 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
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| CN104341410A (en) * | 2013-08-09 | 2015-02-11 | 上海科胜药物研发有限公司 | New Dasatinib crystal form and preparation method thereof |
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| CN105055327A (en) * | 2015-07-30 | 2015-11-18 | 青岛蓝盛洋医药生物科技有限责任公司 | Dasatinib composite granules capable of treating leukaemia |
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| CN105147687A (en) * | 2015-09-28 | 2015-12-16 | 青岛华之草医药科技有限公司 | Pharmaceutical dasatinib composition capsules for treating leukemia |
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