CN103333138A - Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof - Google Patents
Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof Download PDFInfo
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- CN103333138A CN103333138A CN2013103090683A CN201310309068A CN103333138A CN 103333138 A CN103333138 A CN 103333138A CN 2013103090683 A CN2013103090683 A CN 2013103090683A CN 201310309068 A CN201310309068 A CN 201310309068A CN 103333138 A CN103333138 A CN 103333138A
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Abstract
The invention provides a novel Cabazitaxel crystal form, a preparation method, application and pharmaceutical compositions thereof. As the novel Cabazitaxel crystal form provided by the invention is lower in solvent residue, the phenomena that compositional variation or crystal form transformation occurs due to a solvent can be easily removed during a process that a Cabazitaxel solvate is heated or is stored for a long term and amorphous Cabazitaxel is easy to absorb moisture during a long-term storage process are avoided, and the stability of Cabazitaxel is improved. Proved by research results, the novel Cabazitaxel crystal form is not easy to generate the crystal form transformation. Meanwhile, the preparation method provided by the invention is simple to operate, and complicated crystallization conditions are avoided. The novel Cabazitaxel crystal form, the preparation method, the application and the pharmaceutical compositions thereof are more suitable for industrial applications.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, he matches new crystal, its preparation method, its purposes and pharmaceutical composition to relate in particular to a kind of kappa.
Background technology
His match of kappa is the two wires medicine of the treatment prostate cancer of Sanofi-aventis company research and development, is a kind of chemical partially synthetic taxinane micromolecular compound.U.S. FDA is ratified its listing in June, 2010, previously accepted a kind of transitivity hormone refractoriness patients with prostate cancer that contains the treatment of docetaxel treatment plan with the prednisone combination therapy.
His cas number of match of kappa is 183133-96-2, and English name is cabazitaxel,, structural formula is shown in formula I:
Because he matches good curative effect kappa, the researchist has carried out many research to it, stability based on crystal formation is better than unformed common understanding usually, the researchist has developed the multiple crystal formation of his match of kappa, and conclusion gets up to have following several: solvated compounds, anhydride, hydrate and amorphous article etc.As US Patent No. 2005065138 reported a kind of kappa he the match acetone solvate, namely A crystal formation kappa he the match; World patent WO2009115655 has reported by his acetone solvate of match of kappa and has heated anhydride, ethylate and the hydrate that obtains, comprised B crystal formation, C crystal formation, D crystal formation, E crystal formation and F crystal formation etc.; Chinese patent CN102675257A reported and a kind ofly frozen by acetone and water-cooled, again the kappa that obtained in 48 hours of drying under reduced pressure he match the crystallized form of anhydride.Though he match has obtained that he matches better stability than unformed kappa above-mentioned crystal formation kappa, it has the acetone equal solvent residual easily, and preparation method's operation is comparatively complicated, is not easy to realize suitability for industrialized production.
Summary of the invention
He matches new crystal, its preparation method, its purposes and pharmaceutical composition to the object of the present invention is to provide a kind of kappa, kappa provided by the invention he to match the new crystal solvent residual amount low, good stability, and the preparation method is easy and simple to handle.
He matches new crystal to the invention provides a kind of kappa, and its X-ray powder diffraction figure shows the characteristic peak that is positioned at 7.21,8.04,10.18,9.76,11.04,12.62,12.92,17.14,17.53,18.46,18.70,21.88 and 22.54 ° of 2 θ.
Preferably, solvent is below 0.25%.
The present invention also provide a kind of kappa he match the preparation method of new crystal, may further comprise the steps:
A) he matches crystallization in methylene dichloride and normal heptane with kappa, and he matches new crystal to obtain kappa.
Preferably, described step a) is specially:
His match of kappa is dissolved in the methylene dichloride, adds normal heptane under the agitation condition, he matches new crystal to obtain kappa after the crystallization.
Preferably, described crystallization is specially:
Carry out still aging, filtration, washing and vacuum drying processing successively with adding the solution that obtains after the normal heptane.
Preferably, he matches acetone solvate, kappa he matches anhydride, kappa he matches ethylate or kappa he matches hydrate his match of described kappa for his match of amorphous kappa, kappa.
Preferably, the volume ratio of described methylene dichloride and normal heptane is 1:1～1:4, and the quality of his match of described kappa and the ratio of the volume of described methylene dichloride are 1～3g:8～15mL.
Preferably, the temperature of described crystallization is 10 ℃～40 ℃.
The present invention also provide the described kappa of a kind of technique scheme he match the purposes of new crystal in the medicine of preparation treatment prostate cancer.
The present invention also provides a kind of pharmaceutical composition, and he matches new crystal and pharmaceutically acceptable carrier to comprise the described kappa of technique scheme.
Compared with prior art, kappa provided by the invention he to match the new crystal dissolvent residual lower, avoided kappa he match solvate be heated or the standing storage process in slough easily solvent generation composition change or take place that crystal formation transforms and unformed kappa he match in the standing storage process problem of the moisture absorption easily, improved his stability of matching of kappa.Result of study shows that his match of new crystal kappa is not easy to take place the conversion of crystal kenel.Simultaneously, preparation method provided by the invention is simple to operate, has avoided complicated, loaded down with trivial details crystallization treatment condition, is more suitable for industrial application.
Description of drawings
He matches the powder X-ray-diffractogram of new crystal the kappa that Fig. 1 obtains for the embodiment of the invention.
Embodiment
He matches new crystal to the invention provides a kind of kappa, and its X-ray powder diffraction figure shows the characteristic peak that is positioned at 7.21,8.04,10.18,9.76,11.04,12.62,12.92,17.14,17.53,18.46,18.70,21.88 and 22.54 ° of 2 θ.
He matches kappa provided by the invention in the new crystal, and solvent is below 0.25%.
Kappa provided by the invention he to match the new crystal dissolvent residual lower, avoided kappa he match solvate be heated or the standing storage process in slough easily solvent generation composition change or take place that crystal formation transforms and unformed kappa he match in the standing storage process problem of the moisture absorption easily, improved his stability of matching of kappa.Result of study shows that his match of new crystal kappa is not easy to take place the conversion of crystal kenel.
The present invention also provide a kind of kappa he match the preparation method of new crystal, may further comprise the steps:
A) he matches crystallization in methylene dichloride and normal heptane with kappa, and he matches new crystal to obtain kappa.
He matches crystallization in methylene dichloride and normal heptane with kappa in the present invention, and he matches new crystal can to obtain kappa, and this process is specially:
His match of kappa is dissolved in the methylene dichloride, adds normal heptane under the agitation condition, he matches new crystal to obtain kappa after the crystallization.
The present invention does not have particular restriction to described his form of match of pending kappa, can be his match of kappa of any crystal formation, he matches acetone solvate, kappa he matches anhydride, kappa he matches ethylate or kappa he matches hydrate etc. as his match of amorphous kappa, kappa.
The present invention at first is dissolved in his match of kappa in the methylene dichloride, adds normal heptane in the solution that obtains then under stirring condition, and he matches new crystal can to obtain kappa after the crystallization.In the present invention, the volume ratio of described methylene dichloride and normal heptane is preferably 1:1～1:4, more preferably 1:2; The quality of his match of described kappa and the ratio of the volume of described methylene dichloride are preferably 1～3g:8～15mL, more preferably 2g:10mL.Preferably he matches and adds normal heptane in the dichloromethane solution to kappa under 10 ℃～40 ℃ condition in the present invention, and described temperature is room temperature more preferably.
Particularly, the present invention to kappa he match in the dichloromethane solution add normal heptane after, with the solution left standstill ageing that obtains, described still aging temperature is preferably 10 ℃～40 ℃, more preferably room temperature; The described still aging time is preferably 0.5～3h, more preferably 1h.
Behind still aging the finishing, filter, with the precipitation that the normal heptane washing obtains, should precipitate then and can obtain kappa after the vacuum-drying he matches new crystal.
After obtaining kappa he matching new crystal, adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument, at test parameter be: the copper target, pipe stream 150mA, pipe is pressed 40kV, 8 °/minute of sweep velocitys, under the condition that step-length is 0.02 ° it is analyzed, the result shows, its powder diagram (PXRD) shows the characteristic peak that is positioned at 7.21,8.04,10.18,9.76,11.04,12.62,12.92,17.14,17.53,18.46,18.70,21.88 and 22.54 ° of 2 θ, he matches crystal to be different from the existing disclosed kappa of document, belongs to new crystal.
After obtaining kappa he matching new crystal, it is carried out GC detect, the result shows that its normal heptane content is below 0.25%.
After obtaining kappa he matching new crystal, under 60 ℃ it is heated, its single foreign matter content increasing amount is 0.01% after 10 days, and total impurities content increasing amount is 0.05%, and the result shows that it is comparatively stable under heating condition.
After obtaining kappa he matching new crystal, it is prepared into injection liquid, according to " chemicals bioequivalence investigative technique governing principle " disclosed method, be that reference preparation is measured kappa he is matched the drug effect of new crystal injection liquid with JEVTANA, the result shows, the drug effect of itself and reference preparation JEVTANA does not have significant difference.
The present invention is dissolved in his match of kappa in the methylene dichloride, adds normal heptane under the agitation condition, and he matches new crystal to obtain kappa after the crystallization, and this preparation method is simple to operate, has avoided complicated, loaded down with trivial details crystallization treatment condition, is more suitable for industrial application.
The present invention also provide the described kappa of a kind of technique scheme he match the purposes of new crystal in the medicine of preparation treatment prostate cancer.
The present invention also provides a kind of pharmaceutical composition, and he matches new crystal and pharmaceutically acceptable carrier to comprise the described kappa of technique scheme.
The present invention to described pharmaceutically acceptable carrier without any restriction, those skilled in the art can be according to kappa his the concrete preparation of matching new crystal select, as, when he matched new crystal and is prepared as injection with kappa, described pharmaceutically acceptable carrier can be solvent.In addition, can also comprise pharmaceutically acceptable vehicle or auxiliary material etc., the present invention there is no particular restriction to this.
Accordingly, pharmaceutical composition provided by the invention also can be used for the treatment of prostate cancer.
In order to further specify the present invention, he matches new crystal, its preparation method, its purposes and pharmaceutical composition and describes in detail to kappa provided by the invention below in conjunction with embodiment, but they can not be interpreted as the restriction to protection domain of the present invention.
Take by weighing his match of the unformed kappa of 2.0g and be dissolved in the 10.0ml methylene dichloride, drip the 40.0ml normal heptane under the stirring at room, still aging 1h filters, and solid washs with a small amount of normal heptane, gets 1.85g solid product, yield 92.5% after the vacuum-drying.
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument, at test parameter be: the copper target, pipe stream 150mA, pipe is pressed 40kV, 8 °/minute of sweep velocitys, under the condition that step-length is 0.02 ° described solid product is analyzed, the result is referring to Fig. 1, and he matches the powder X-ray-diffractogram of new crystal the kappa that Fig. 1 obtains for the embodiment of the invention.As shown in Figure 1, its powder diagram (PXRD) shows the characteristic peak that is positioned at 7.21,8.04,10.18,9.76,11.04,12.62,12.92,17.14,17.53,18.46,18.70,21.88 and 22.54 ° of 2 θ, he matches crystal to be different from the existing disclosed kappa of document, belongs to new crystal.
Described solid product is carried out GC detect, its normal heptane content is 0.24%.
Embodiment 2
His match of 2.0gA crystal formation kappa is dissolved in the 10.0ml methylene dichloride, drips the 40.0ml normal heptane under the stirring at room, still aging 1h filters, and solid washs with a small amount of normal heptane, gets 1.78g solid product, yield 89.0% after the vacuum-drying.
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument that described solid product is analyzed, the result shows that it is consistent with the product crystal formation that embodiment 1 prepares.
Described solid product is carried out GC detect, its normal heptane content is 0.23%.
Embodiment 3
His match of 2.0gB crystal formation kappa is dissolved in the 10.0ml methylene dichloride, drips the 40.0ml normal heptane under the stirring at room, still aging 1h filters, and solid washs with a small amount of normal heptane, gets 1.80g solid product, yield 90.0% after the vacuum-drying.
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument that described solid product is analyzed, the result shows that it is consistent with the product crystal formation that embodiment 1 prepares.
Described solid product is carried out GC detect, its normal heptane content is 0.21%.
Embodiment 4
He matches ethylate and is dissolved in the 10.0ml methylene dichloride with the 2.0g kappa, drips the 20.0ml normal heptane under the stirring at room, and still aging 1h filters, and solid washs with a small amount of normal heptane, must the 1.82g solid product after the vacuum-drying, and yield 91.0%.
Adopt Japanese Rigaku D/max-2550 powder x-ray diffraction instrument that described solid product is analyzed, the result shows that it is consistent with the product crystal formation that embodiment 1 prepares.
Described solid product is carried out GC detect, its normal heptane content is 0.20%.
Embodiment 5 stability tests
He matches sample the crystalline state kappa that he matches and embodiment 2 obtains with A crystal formation kappa, uncoveredly respectively divide placement, investigation is stability of sample under 60 ℃ of conditions of heating, investigating sample time is 10 days, HPLC detects purity and sees Table 1, and he matches the stability test result of crystal the kappa that table 1 provides for the embodiment of the invention and comparative example.
He matches the stability test result of crystal the kappa that table 1 embodiment of the invention and comparative example provide
As shown in Table 1, he matches his match of crystalline state kappa provided by the invention and A crystal formation kappa, and is under 60 ℃ of conditions of high temperature, more stable.
Embodiment 6 effect experiments
His match of kappa of embodiment 2 preparation is mixed with Tween-80, Citric Acid, and the ethanolic soln with 13% is that solvent is mixed with kappa he matches injection;
According to " chemicals bioequivalence investigative technique governing principle ", the blood plasma pharmacokinetics feature that he matches behind injection and the reference preparation JEVTANA to the kappa of the Beagle dog single intravenous drip embodiment of the invention 2 preparation is studied.The result shows, he matches injection (being subjected to test preparation) and JEVTANA(reference preparation the kappa of the Beagle dog intravenous drip embodiment of the invention 2 preparation) afterwards Plasma Concentration more than administration after 0.5h reach the peak, the 1.5-3h Plasma Concentration is reduced to the 1/10-1/20 of peak concentration respectively after the administration, and 25h is near lowest detectable limit after the administration.He matches injection and JEVTANA(reference preparation the kappa of the Beagle dog intravenous drip embodiment of the invention 2 preparation) after reach peak concentration (measured value) and be respectively 162.16 ± 60.82ng/mL and 156.72 ± 53.64ng/mL, AUC (0-t) is respectively 271.50 ± 99.42 μ g/L*h and 284.15 ± 97.70 μ g/L*h, and average retention time MRT (0-t) is respectively 2.54 ± 1.77h and 2.37 ± 1.51h in the body.In the Beagle dog body kappa of the embodiment of the invention 2 preparations he match injection (being subjected to test preparation) AUC (0-t) and be the 93.6%(fiducial interval 82.1%-106.8% of reference preparation JEVTANA), Cmax is the 103.4%(fiducial interval 84.5%-126.4% of reference preparation JEVTANA); MRT (0-t), t1/2z compare with reference preparation JEVTANA with Tmax does not all have significant difference.
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
- A kappa he match new crystal, its X-ray powder diffraction figure shows the characteristic peak that is positioned at 7.21,8.04,10.18,9.76,11.04,12.62,12.92,17.14,17.53,18.46,18.70,21.88 and 22.54 ° of 2 θ.
- Kappa according to claim 1 he match new crystal, it is characterized in that solvent is below 0.25%.
- A kappa he match the preparation method of new crystal, may further comprise the steps:A) he matches crystallization in methylene dichloride and normal heptane with kappa, and he matches new crystal to obtain kappa.
- 4. preparation method according to claim 3 is characterized in that, described step a) is specially:His match of kappa is dissolved in the methylene dichloride, adds normal heptane under the agitation condition, he matches new crystal to obtain kappa after the crystallization.
- 5. preparation method according to claim 4 is characterized in that, described crystallization is specially:Carry out still aging, filtration, washing and vacuum drying processing successively with adding the solution that obtains after the normal heptane.
- 6. according to claim 3 or 4 described preparation methods, it is characterized in that he matches acetone solvate, kappa he matches anhydride, kappa he matches ethylate or kappa he matches hydrate his match of described kappa for his match of amorphous kappa, kappa.
- 7. according to claim 3 or 4 described preparation methods, it is characterized in that the volume ratio of described methylene dichloride and normal heptane is 1:1～1:4, the quality of his match of described kappa and the ratio of the volume of described methylene dichloride are 1～3g:8～15mL.
- 8. according to claim 3 or 4 described preparation methods, it is characterized in that the temperature of described crystallization is 10 ℃～40 ℃.
- The described kappa of claim 1 he match the purposes of new crystal in the medicine of preparation treatment prostate cancer.
- 10. pharmaceutical composition, he matches new crystal and pharmaceutically acceptable carrier to comprise the described kappa of claim 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110577507A (en) * | 2019-07-19 | 2019-12-17 | 西安新通药物研究有限公司 | Stable cabazitaxel crystal form and preparation method thereof |
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| WO2013080217A2 (en) * | 2011-11-28 | 2013-06-06 | Fresenius Kabi Oncology Ltd. | Crystalline forms of carbazitaxel and process for preparation thereof |
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| CN102503913A (en) * | 2011-10-20 | 2012-06-20 | 江苏红豆杉生物科技有限公司 | Preparation method for dimethoxy taxanes compound monocrystal directly used for X-ray single crystal diffraction analysis |
| WO2013080217A2 (en) * | 2011-11-28 | 2013-06-06 | Fresenius Kabi Oncology Ltd. | Crystalline forms of carbazitaxel and process for preparation thereof |
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| CN110577507A (en) * | 2019-07-19 | 2019-12-17 | 西安新通药物研究有限公司 | Stable cabazitaxel crystal form and preparation method thereof |
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Application publication date: 20131002 |