CN103058960B - Cabazitaxel polymorphic form and preparation method thereof - Google Patents

Cabazitaxel polymorphic form and preparation method thereof Download PDF

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CN103058960B
CN103058960B CN201210535297.2A CN201210535297A CN103058960B CN 103058960 B CN103058960 B CN 103058960B CN 201210535297 A CN201210535297 A CN 201210535297A CN 103058960 B CN103058960 B CN 103058960B
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cabazitaxel
form
preparation method
characterized
acetone
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CN201210535297.2A
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CN103058960A (en
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赵俊
王孝雯
刘文杰
王易
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江苏奥赛康药业股份有限公司
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Abstract

The invention belongs to the technical field of medicines, relating to a cabazitaxel polymorphic form and a preparation method thereof, and particularly provides a novel crystalline form of anhydride, monohydrate and dehydrate of cabazitaxel and a preparation method thereof. The novel crystalline form provided by the invention is good in product stability, simple in preparation technology, good in quality reproducibility and easy to control for product purity, and is suitable for industrial production.

Description

Cabazitaxel polymorphic forms and preparation method thereof

Technical field

The invention belongs to medical technical field, relate to particularly new Cabazitaxel polymorphic forms and preparation method thereof.

Background technology

Antitumour drug Cabazitaxel; 7,10-bi-methoxy docetaxel, chemistry (2 α by name; 5 β; 7 β, 10 β, 13 α)-4-acetoxyl group-13-({ (2R; 3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxyl-3-hydrocinnamoyl } oxygen)-1-hydroxyl-7; 10-dimethoxy-9-oxo Japanese yew-5,20-epoxy group(ing)-11-alkene-2-benzoic ether, its chemical structural formula is as follows:

Cabazitaxel belongs to taxanes antitumour drug, and it is by using from the semi-synthetic preparation of precursor of Ramulus et folium taxi cuspidatae extraction, being mainly used in treating hormone refractory metastatic prostate cancer.Cabazitaxel is a kind of microtubule inhibitors, by with tubulin binding, promote microtubule dimer to be assembled to microtubule, by preventing that multimerization process from suppressing microtubule and decomposing and make microtubule stable, retardance cell is in G simultaneously 2with the M phase, thus the mitotic division of anticancer and propagation.It has anti-tumor activity to people's knurl in late period of transplanting in mouse, and the responsive tumor line of docetaxel also has activity, in addition, in chemotherapy being comprised to the insensitive tumor model of docetaxel, still has activity.This medicine was gone on the market through preferential examination and approval procedures approval by U.S. FDA on June 17th, 2010, was that it gets the Green Light in the world first specifically, had wide market outlook.

In pharmaceutical production, the specific polymorphic of bulk drug takes advantage in stability, thus in production process, find stability strong, be beneficial to long-term storage and under certain environment, keep in other words the crystal formation of its specific physics, stable chemical nature significant.Patent and patent application about Cabazitaxel crystal formation at present mainly contains ZL200480026128.X, CN101918385A, CN102659722A, CN102675257A etc., acetone solvate crystal formation of the disclosed Cabazitaxel of ZL200480026128.X and preparation method thereof wherein, but not highly stable according to experimental result acetone solvate, under long-term placement or hot conditions, all easily slough part acetone, and the quality of bulk drug also can decline to some extent; Although CN101918385A discloses a variety of crystal formations, its preparation method is very unique, is not suitable for industrialized production; CN102659722A discloses Cabazitaxel amorphous form; CN102675257A discloses a kind of Cabazitaxel anhydrous form crystal.

Summary of the invention

The object of the present invention is to provide three kinds of new Cabazitaxel polymorphic forms, its stable crystal form is good, is difficult for transformation and preparation method's repeatability and circulation ratio better, preparation is simple, easy to operate, be applicable to industrialized production, there is wide industrial prospect and huge industrial value.

One of object of the present invention is to provide a kind of Cabazitaxel anhydrate form, the Cabazitaxel anhydrate form providing in the present invention is carried out to x-ray powder diffraction and test, 2 θ of the X-ray powder diffraction figure obtaining have located diffraction peak at 7.28,8.12,9.84,12.68,13.00,17.64 and 18.56 ± 0.2 °.

Further, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel anhydrate form have located diffraction peak at 7.28,8.12,9.84,10.36,11.10,12.68,13.00,15.86,17.20,17.64,18.56 and 21.98 ± 0.2 °.

Cabazitaxel anhydrate form provided by the invention, its dsc analysis collection of illustrative plates has obvious crystalline exotherm peak at 161.78 ℃; TG analyzes collection of illustrative plates and shows that this crystal formation does not have weightlessness.

The method that the invention provides the described Cabazitaxel anhydrate form of a kind of preferred preparation, comprising: Cabazitaxel acetone solvate is dissolved in acetone, under room temperature, drips water, stirs, and filters, and filter cake washes with water, and vacuum-drying obtains described Cabazitaxel anhydrous form.

Preferably, with respect to every gram of Cabazitaxel acetone solvate, the consumption of described acetone is 10~20ml, and in described reaction, the consumption of water is 100~200ml.

Another object of the present invention is to provide a kind of new Cabazitaxel monohydrate form, the Cabazitaxel monohydrate form providing in the present invention is carried out to x-ray powder diffraction and test, 2 θ of the X-ray powder diffraction figure obtaining have located diffraction peak at 8.82,11.02,13.94,17.74 and 19.34 ± 0.2 °.

Further, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel monohydrate form have located diffraction peak at 8.82,10.32,11.02,12.42,13.94,15.36,17.74,18.42,19.34,19.78 and 23.28 ± 0.2 °.

Further, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel monohydrate form have located diffraction peak at 4.42,7.24,8.24,8.82,10.32,11.02,12.42,13.00,13.42,13.94,15.36,16.52,17.18,17.74,18.42,19.34,19.78,20.38 and 21.38 ± 0.2 °.

Cabazitaxel monohydrate form provided by the invention, its dsc analysis collection of illustrative plates has obvious crystalline exotherm peak at 150.20 ℃; TG analyzes collection of illustrative plates and shows that this crystal formation weightlessness is 1.9 ± 0.1%.

The method that the invention provides the described Cabazitaxel monohydrate of a kind of preferred preparation form, comprising: Cabazitaxel acetone solvate is dissolved in ethanol, under room temperature, drips water, stir, filter, filter cake washes with water, and vacuum-drying obtains described Cabazitaxel monohydrate form.

Preferably, with respect to every gram of Cabazitaxel acetone solvate, the consumption of described ethanol is 10~20ml, and in described reaction, the consumption of water is 100~200ml.

Another object of the present invention is to provide a kind of new Cabazitaxel dihydrate form, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel dihydrate form have located diffraction peak at 7.46,7.80,10.16,17.68 and 19.68 ± 0.2 °.

Further, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel dihydrate form have located diffraction peak at 7.46,7.80,10.16,12.60,12.82,14.42,17.00,17.68,18.14,19.68 and 21.94 ± 0.2 °.

Further, 2 θ of the X-ray powder diffraction figure of described Cabazitaxel dihydrate form have located diffraction peak at 7.46,7.80,10.16,12.60,12.80,13.40,14.42,17.00,17.68,18.14,19.68,21.08,21.62 and 21.94 ± 0.2 °.

Cabazitaxel dihydrate form provided by the invention, its dsc analysis collection of illustrative plates has obvious crystalline exotherm peak at 156.17 ℃; TG analyzes collection of illustrative plates and shows that this crystal formation weightlessness is 4.4 ± 0.1%.

The method that the invention provides the described Cabazitaxel monohydrate of a kind of preferred preparation form, comprising: Cabazitaxel acetone solvate is dissolved in tetrahydrofuran (THF), under room temperature, drips water, stir, filter, filter cake washes with water, and vacuum-drying obtains described Cabazitaxel dihydrate form.

Preferably, with respect to every gram of Cabazitaxel acetone solvate, the consumption of described tetrahydrofuran (THF) is 10~20ml, and in described reaction, the consumption of water is 100~200ml.

The preparation of above-mentioned Cabazitaxel acetone solvate can referenced patent ZL200480026128.X embodiment 1.Above-mentioned " consumption of water in reaction " refers to the consumption of water in " dripping water under room temperature " operation; Above-mentioned institute water is preferably purified water.

The invention provides the crystalline forms of three kinds of Cabazitaxels, three kinds of crystalline forms are all more stable, and under hot and humid environment, crystal formation does not change, and purity and stable content are all better, single assorted very little; And preparation method's repeatability and circulation ratio are better, simple to operation, very little to environment and personnel's harm, be applicable to industrialized production.

Accompanying drawing explanation:

Fig. 1 is the XRPD figure of Cabazitaxel anhydrate form of the present invention

Fig. 2 is the DSC figure of Cabazitaxel anhydrate form of the present invention

Fig. 3 is the TG figure of Cabazitaxel anhydrate form of the present invention

Fig. 4 is the XRPD figure of Cabazitaxel monohydrate form of the present invention

Fig. 5 is the DSC figure of Cabazitaxel monohydrate form of the present invention

Fig. 6 is the TG figure of Cabazitaxel monohydrate form of the present invention

Fig. 7 is the XRPD figure of Cabazitaxel dihydrate form of the present invention

Fig. 8 is the DSC figure of Cabazitaxel dihydrate form of the present invention

Fig. 9 is the TG figure of Cabazitaxel dihydrate form of the present invention

Embodiment

The more detailed description that following embodiment just carries out invention, not should be understood to be to scope of the present invention or ask for protection the restriction of scope.

In the present invention, related XPRD all adopts Swiss X'TRA type X-ray diffractometer, and condition determination is copper target, tube voltage 40kV, tube current 100mA, 10.00 °/min of sweep velocity, 3.00~45.00 ° of sweep limits.

DSC and TG related in the present invention all adopt U.S. Perkin Elmer company to produce PYRTS-1-DSC type thermal analyzer, and TGA test condition is heat-up rate: 20 ° of C/min; Temperature range: 25 ° of C~700 ° C; DSC test condition is heat-up rate: 10 ° of C/min; Temperature range: 50 ° of C~300 ° C.

In the present invention, the analysis liquid-phase condition of the purity testing of related product is: all adopt Japanese Shimadzu LC/20AT high performance liquid phase detector, add the alkyl linked silicagel column of Rec C18, specification 250*4.6mm, post footpath 5 μ m, detection wavelength is 230nm, and moving phase is acetonitrile/methanol=45:55.

Embodiment 1

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 5ml acetone, under room temperature, in above-mentioned solution, drip 50ml purified water, have a large amount of white solids.After at room temperature stirring 30min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 458mg, yield 98.0%; The XPRD spectrogram of this product is shown in Fig. 1, and DSC spectrogram is shown in Fig. 2, and TGA spectrogram is shown in Fig. 3, and according to spectrogram and data judgement, this compound is Cabazitaxel anhydrate form.

Embodiment 2

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 10ml acetone, under room temperature, in above-mentioned solution, drip 100ml purified water, have a large amount of white solids.After at room temperature stirring 45min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 452mg, yield 96.6%; The XPRD of this product, DSC spectrogram, TGA spectrogram are substantially the same manner as Example 1, and product is Cabazitaxel anhydrate form.

Embodiment 3

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 5ml ethanol, under room temperature, in above-mentioned solution, drip 50ml purified water, have a large amount of white solids.After at room temperature stirring 30min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 459mg, yield 96.2%; The XPRD spectrogram of this product is shown in Fig. 4, and DSC spectrogram is shown in Fig. 5, and TGA spectrogram is shown in Fig. 6, and residual by organic solvent-free in this crystal formation of vapor detection, and according to spectrogram and data judgement, this product is Cabazitaxel monohydrate form.

Embodiment 4

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 10ml ethanol, under room temperature, in above-mentioned solution, drip 100ml purified water, have a large amount of white solids.After at room temperature stirring 60min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 465mg, yield 97.4%; The XPRD of this product, DSC spectrogram, TGA spectrogram and embodiment 3 products are basic identical, and product is Cabazitaxel monohydrate form.

Embodiment 5

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 5ml tetrahydrofuran (THF), under room temperature, in above-mentioned solution, drip 50ml purified water, have a large amount of white solids.After at room temperature stirring 30min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 471mg, yield 96.5%; The XPRD spectrogram of this product is shown in Fig. 7, and DSC spectrogram is shown in Fig. 8, and TGA spectrogram is shown in Fig. 9, and residual by organic solvent-free in this crystal formation of vapor detection, and according to spectrogram and data judgement, this product is Cabazitaxel dihydrate form.

Embodiment 6

Take Cabazitaxel acetone solvate 500mg stirring and be dissolved in 10ml tetrahydrofuran (THF), under room temperature, in above-mentioned solution, drip 100ml purified water, have a large amount of white solids.After at room temperature stirring 45min, filter, purified water washing is 3 times for the white filter cake obtaining, after vacuum-drying white solid powder 465mg, yield 95.3%; The XPRD of this product, DSC spectrogram, TGA spectrogram are substantially the same manner as Example 5, and product is Cabazitaxel dihydrate form.

Embodiment 7 Cabazitaxel polymorphic forms Detection of Stability

1, high temperature experiment

The Cabazitaxel crystalline forms that the present invention is made is positioned in the vial of sealing clean, is placed in 60 ℃ of thermostatic drying chambers, and respectively sampling in 5,10 days detects, and contrasts with the result of 0 day, the results are shown in Table 1,

Table 2 and table 3:

The experiment of table 1 Cabazitaxel anhydrate form high temperature

The experiment of table 2 Cabazitaxel monohydrate form high temperature

The experiment of table 3 Cabazitaxel dihydrate form high temperature

2, high humidity experiment

The Cabazitaxel crystalline forms that the present invention is made is evenly shared to uncovered culture dish, and thickness≤5mm is placed in room temperature (25 ℃ of left and right), relative humidity is in 75 ± 5% constant incubator, respectively sampling in 5,10 days detects, and contrasts with the result of 0 day, the results are shown in Table 4, table 5 and table 6:

The experiment of table 4 Cabazitaxel anhydrate form high humidity

The experiment of table 5 Cabazitaxel monohydrate form high humidity

The experiment of table 6 Cabazitaxel dihydrate form high humidity

Stability experiment result shows, Cabazitaxel anhydrate form of the present invention, and under hot and humid environment, crystal formation does not change, and purity and stable content are all better, single assorted very little; Cabazitaxel monohydrate form and Cabazitaxel dihydrate form, under hot and humid environment, crystal formation does not change, and related substance does not have considerable change, and single assorted less, content only has reduction slightly; Experimental result shows that three kinds of crystalline forms of the resulting Cabazitaxel of the present invention are all more stable.

Claims (6)

1. a Cabazitaxel anhydrate form, is characterized in that, 2 θ of its X-ray powder diffraction figure exist
7.28, located diffraction peak for 8.12,9.84,10.36,11.10,12.68,13.00,15.86,17.20,17.64,18.56 and 21.98 ± 0.2 °.
2. Cabazitaxel anhydrate form according to claim 1, is characterized in that, its dsc analysis collection of illustrative plates has obvious crystalline exotherm peak at 161.78 ℃.
3. according to the preparation method of the arbitrary described Cabazitaxel anhydrate form of claim 1 to 2, comprising: Cabazitaxel acetone solvate is dissolved in acetone, under room temperature, drip water, stir, filter, filter cake washes with water, and vacuum-drying obtains described Cabazitaxel anhydrous form.
4. preparation method according to claim 3, is characterized in that, with respect to every gram of Cabazitaxel acetone solvate, the consumption of described acetone is 10~20ml, the consumption 100~200ml of water in described reaction.
5. a Cabazitaxel dihydrate form, it is characterized in that, 2 θ of its X-ray powder diffraction figure have located diffraction peak at 7.46,7.80,10.16,12.60,12.80,13.40,14.42,17.00,17.68,18.14,19.68,21.08,21.62 and 21.94 ± 0.2 °.
6. Cabazitaxel dihydrate form according to claim 5, is characterized in that, its dsc analysis collection of illustrative plates has obvious crystalline exotherm peak at 156.17 ℃.
CN201210535297.2A 2012-12-12 2012-12-12 Cabazitaxel polymorphic form and preparation method thereof CN103058960B (en)

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CN106674157A (en) * 2016-12-19 2017-05-17 扬子江药业集团广州海瑞药业有限公司 Novel cabazitaxel anhydrous compound and preparation method and crystal form thereof

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US9394266B2 (en) 2012-03-08 2016-07-19 IVAX International GmbH Solid state forms of cabazitaxel and processes for preparation thereof
CN102746258B (en) 2012-07-25 2015-02-04 重庆泰濠制药有限公司 Crystal forms of cabazitaxel and preparation method thereof
CN103044364B (en) * 2013-01-07 2016-01-20 重庆泰濠制药有限公司 Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof
WO2015000165A1 (en) * 2013-07-04 2015-01-08 北京新天宇科技开发有限公司 Stable transformation product of dimethoxy docetaxel mono-acetonate and crystalline forms thereof, and methods for preparation of same
CN103333138A (en) * 2013-07-22 2013-10-02 北京科莱博医药开发有限责任公司 Novel Cabazitaxel crystal form, preparation method, application and pharmaceutical compositions thereof
CN103450119B (en) * 2013-09-24 2015-06-17 天津炜捷制药有限公司 Cabazitaxel with crystal form W and method for preparing same

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