KR101429543B1 - A novel crystal form of cabazitaxel and a method for preparing the same - Google Patents

Abstract

More particularly, the present invention relates to a new crystal form of a cabbage tablet, which has no humectancy and does not change in crystal form, and which has improved stability and is thus easy to store, a method for producing the same, The present invention relates to an industrially useful method which can easily manufacture a cabbage tablet in an improved stability form.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel crystal form of a cabbage tablet and a preparation method thereof,

More particularly, the present invention relates to a new crystal form of a cabbage tablet, which has no humectancy and does not change in crystal form, and which has improved stability and is thus easy to store, a method for producing the same, The present invention relates to an industrially useful method which can easily manufacture a cabbage tablet in an improved stability form.

Carbazetaxel, 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 10β-dimethoxy-9-oxo-tax-11- tert-butoxycaronylamino-2-hydroxy-3-phenylpropionate) is a taxoid-based semisynthetic compound having a structure represented by the following general formula (1), and has broad anti-cancer activity and anti-leukemia characteristics. In recent years, It has been approved by the Food and Drug Administration (FDA) for the treatment of hormone-refractory prostate cancer (HRPC) and is being marketed under the name Jevtana®.

[Chemical Formula 1]

WO 96/30355 and WO 99/25704 disclose a method for the synthesis of cabazetaxel. WO 2005/028462 discloses a process for producing an acetone solvate of cabbage taxol and a crystal form thereof (acetone solvate crystal form A, Formula 2 below).

(2)

WO 2009/115655 also discloses anhydrous, ethanol heterolysate, and hydrate crystal form of cabbage taxane and a process for preparing the same.

However, the results obtained by the methods disclosed in the prior art describe that the anhydrous D-form is most stable when stored at 40 < 0 > C for 4 weeks. Further, the acetone solvate A is described as having a problem of desolvation resulting in a mixture of acetone solvate A and anhydrous B.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made to solve the above problems of the prior art, and it is an object of the present invention to provide a novel crystalline form of a cabbage tablet, which has no habitability, It is a technical problem to provide industrially very useful methods.

In order to solve the above technical problems, a first aspect of the present invention provides an ethyl acetate solvate of cabbage tablet.

According to a preferred embodiment of the present invention, the ethyl acetate solvate of the cabbage tablet is crystalline.

According to a second aspect of the present invention there is provided a process for the preparation of a crystalline carbapentase, comprising the steps of: (1) dissolving carbacytax in ethyl acetate, and (2) A method for manufacturing a cargo crystal is provided.

According to a third aspect of the present invention there is provided a process for the preparation of carbamates, comprising the steps of: (1) dissolving carbazatocelles in a solvent selected from dichloromethane, methanol and mixtures thereof, (2) concentrating the resultant solution of step (1) ) A process for producing amorphous cabbage tablet comprising the step of obtaining a carbazate tablet in solid form from the resulting concentrate of step (2).

According to a fourth aspect of the present invention there is provided a method for preparing a cosmetic composition comprising the steps of: (1) dissolving cabbage tablet in a solvent selected from dichloromethane, methanol and mixtures thereof, and (2) The method comprising the steps of:

According to a fifth aspect of the present invention, there is provided an amorphous cabinet tablet cell characterized by being manufactured by the method of the third aspect or the fourth aspect.

According to a sixth aspect of the present invention, there is provided a process for preparing a crystalline carbazate compound, comprising the steps of: (1) dissolving cabbage bath in a solvent selected from dichloromethane, acetone and a mixture thereof, and (2) adding hexane or heptane to the resultant solution To form a crystalline carbazatocelic anhydride.

According to a seventh aspect of the present invention, there is provided an anhydrous crystal of cabbage taxa characterized by being produced by the method of the sixth aspect.

The forms of the cabbage tablet according to the present invention are excellent in stability with no change in the HPLC purity even after being maintained at 60 DEG C for 10 weeks and in such a degree that changes in the powder X-ray diffraction (PXRD) spectrum are not detected, , The ethyl acetate solvate crystal of the cabbage tablet according to the present invention is not humidified even after being left in a chamber at 25 DEG C and a relative humidity of 60% for 7 days (initial water content: 0.2 wt% or less, water content: 0.2 wt% or less after 7 days ). Therefore, according to the present invention, the cabbage tablet can be easily manufactured in a form which is excellent in stability and can be easily stored, which is very industrially useful.

1 is a powder X-ray diffraction (PXRD) spectrum of amorphous carbide tablet obtained in Example 1-1.
2 is an infrared spectroscopy (IR) spectrum of the amorphous cabbage tablet prepared in Example 1-1.
Fig. 3 is a result of differential scanning calorimetry (DSC) of the amorphous cabbage tablet produced in Example 1-1.
4 is a thermogravimetric analysis (TGA) result of the amorphous cabbage tablet prepared in Example 1-1.
5 is a powder X-ray diffraction (PXRD) spectrum of anhydrous calcium cabbage prepared in Example 2-1.
6 is an infrared spectroscopy (IR) spectrum of the calcareous taxane crystals prepared in Example 2-1.
7 is a result of differential scanning calorimetry (DSC) of anhydrous calcium cabbage prepared in Example 2-1.
8 is a thermogravimetric analysis (TGA) result of anhydrous calcium caspase prepared in Example 2-1.
9 is a powder X-ray diffraction (PXRD) spectrum of the ethyl acetate solvate of the cabbage tablet prepared in Example 3-2.
10 is an infrared spectroscopy (IR) spectrum of the ethyl acetate solvate of the cabbage tablet prepared in Example 3-2.
11 is a result of differential scanning calorimetry (DSC) of ethyl acetate solvate of cabbage tablet prepared in Example 3-2.
12 is a thermogravimetric analysis (TGA) result of the ethyl acetate solvate of the cabbage tablet prepared in Example 3-2.

Hereinafter, the present invention will be described in more detail.

I. Cabot of Texel  Ethyl acetate solvate

According to one aspect of the present invention, there is provided an ethyl acetate solvate of cabbage tablet.

The ethyl acetate solvate of the cabbage tablet according to a preferred embodiment of the present invention is crystalline.

According to one embodiment of the present invention, the ethyl acetate solvate crystal of carbajtaxel has 2? Values on the powder X-ray diffraction (PXRD) spectrum of 7.4, 7.8, 8.6, 9.9, 10.1, 12.6, 12.8, 13.3, 13.7, 14.0, 14.6, 14.9, 15.8, 16.4, 17.0, 17.3 and 17.9 ± 0.2 °, and melting point by differential scanning calorimetry (DSC) is 154 ± 0.3 ° C.

The ethyl acetate solvate crystals of the carbapatocells of the present invention can be prepared by a process comprising: (1) dissolving cabbage taxol in ethyl acetate, and (2) producing crystals from the resulting solution of step (1) .

In the step (1), the cabbage bath is completely dissolved in ethyl acetate. Preferably, it is dissolved under reflux using about 20 to 40 mL of ethyl acetate per gram of carbapataxel. The resulting solution is filtered as necessary and used in the next step.

In the step (2), crystals can be generated while cooling the resultant solution of the step (1). At this time, the temperature of the solution is preferably maintained at 10 to 30 ° C, and crystals can be produced under stirring at this temperature for about 1 hour to 20 hours, more preferably for 1 hour to 2 hours.

Alternatively, hexane or heptane may be added as an anti-solvent to the resultant solution of step (1) to form crystals. Preferably, about 40 to 60 mL of hexane or heptane per g of carbapentex can be used. In addition, the volume ratio of ethyl acetate: hexane or heptane half-solvent is preferably 1: 1 to 1: 1.5, most preferably 1: 1. According to one preferred embodiment of the invention, 40 mL of ethyl acetate and 40 mL of hexane or heptane half-solvent are used per g of cabazitabaxel.

After the addition of the semi-solvent, crystals can be produced by slurrying the resulting mixture, preferably at -20 to 30 占 폚, more preferably at 15 to 25 占 폚.

The ethyl acetate solvate crystals of the carbapatite thus produced may be vacuum-dried after filtration, for example, at 20 to 40 ° C for 1 to 8 hours. According to a preferred embodiment of the present invention, the ethyl acetate solvate crystal of the carbajtaxel obtained after vacuum drying has a water content of 0.2% by weight or less and an ethyl acetate content of 9.1 to 9.7% by weight With an ethyl acetate stoichiometric content of about 9.5% by weight).

II . Amorphous Cabotaxel

According to another aspect of the present invention, there is provided a method of manufacturing an amorphous cabinet tablet.

In one embodiment of the present invention, there is provided a process for preparing a cosmetic composition comprising the steps of: (1) dissolving cabbage tablet in a solvent selected from dichloromethane, methanol and mixtures thereof, (2) concentrating the resulting solution of step (1) And a step of obtaining the carbage tablet from the resulting concentrate of step (2) in the form of a solid, to prepare amorphous cavid tablet.

In another embodiment of the present invention, the method comprises the steps of (1) dissolving in a solvent selected from dichloromethane, methanol, and mixtures thereof, and (2) obtaining the cabazetaxel in solid form from the resultant solution of step (1) To make an amorphous cabbage tablet.

There is no particular limitation on the amount of solvent used in the step of dissolving cabbage taxane in a solvent selected from dichloromethane, methanol and a mixture thereof, and preferably about 1 to 100 mL, more preferably about 5 to 100 mL per 1 g of cabazataxel, And dissolved under reflux using 60 mL of a solvent. The resulting solution is filtered as necessary and used in the next step.

Next, after the cabbage bath solution thus obtained is concentrated, the cabbage tablet can be obtained in the form of a solid from the concentrate. Concentration of the cabbage bath solution can be carried out in a conventional concentration under reduced pressure, resulting in an oil-phase concentrate. As a method of obtaining the cabazetaxel in the solid form from the concentrate, there is a method of immediately drying the concentrate in vacuum or a method of adding precipitates to the concentrate by adding hexane or heptane as an anti-solvent and filtering and vacuum drying the resulting precipitate Can be used. When an anti-solvent is used, preferably about 10 to 80 mL, more preferably about 20 to 60 mL, of hexane or heptane can be used per 1 g of cabazitabax, and after the addition of an anti-solvent, The slurry can be slurried at 30 DEG C, more preferably at 15 DEG C to 25 DEG C to produce a precipitate. Vacuum drying can be carried out at 50 to 70 DEG C for 10 to 60 hours

Alternatively, the cabazetaxel can be obtained in solid form directly from the cabazitabaxel solution. In this case, it is preferable to use a method of forming a precipitate by allowing the carbazatexel solution to stand at a low temperature, for example, -40 to -15 DEG C for 10 to 48 hours, filtering the resulting precipitate, or drying the cabazitabaxel solution, Drying method can be used to obtain a cabbage tablet in solid form. The obtained solid form of cabbage bath can be vacuum-dried under the above-mentioned conditions. The melting point of amorphous carbide tablet obtained by differential scanning calorimetry (DSC) is 131 ± 0.2 ° C.

III . Cabotaxel  Anhydrous crystals

According to another aspect of the present invention, there is provided a process for producing anhydrous crystalline carbajsacite.

In one embodiment of the present invention, there is provided a method for preparing a crystalline carbamate compound, comprising the steps of: (1) dissolving cabbage taxane in a solvent selected from dichloromethane, acetone and a mixture thereof, and (2) adding hexane or heptane to the resultant solution of step Wherein the crystalline carbazate anhydrous crystal is prepared by a method comprising the steps of:

In the step (1), the cabbage bath is completely dissolved in a solvent selected from dichloromethane, acetone and a mixture thereof. Preferably, it is dissolved using about 3 to 10 mL, more preferably 4 to 7 mL of solvent per g of cabazataxel.

In the step (2), hexane or heptane is added as an anti-solvent to the resultant solution of the step (1) to form a crystal. At this time, preferably about 10 to 100 mL, more preferably 15 to 60 mL, of hexane or heptane can be used per 1 g of cabazitabacel. After the addition of the semi-solvent, crystals can be produced by slurrying the resulting mixture, preferably at -20 to 30 占 폚, more preferably at 15 to 25 占 폚.

The dried calcium carbase anhydrous crystals can be filtered and then vacuum-dried at a high temperature, for example, at 50 to 70 ° C for 10 to 60 hours. According to one preferred embodiment of the present invention, the carbazatocelic anhydrous crystals obtained after vacuum drying have a 2-theta value on the powder X-ray diffraction (PXRD) spectrum of 7.2, 8.0, 8.9, 9.7, 10.2, 11.0, 11.8, 12.6, 12.8, 14.2, 15.2, 15.7, 16.2, 17.1, 17.5, 17.9 and 18.4 ± 0.2 ° and the melting point by differential scanning calorimetry (DSC) is 153 ± 0.3 ° C.

Hereinafter, the present invention will be described in more detail by way of examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

[ Example ]

The amorphous or crystalline forms of the cabbage tablet obtained in the following examples were analyzed by powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis using equipment and conditions as shown below. Moisture was measured using the Karl Fischer method.

Powder X-Ray Diffraction (PXRD)

Fourier transform infrared spectroscopy (FT-IR, Fourier transform infrared)

Differential scanning calorimetry (DSC)

Thermogravimetric analysis (TGA)

The cabbage tablet used as a starting material in Example 1 below was the one that was semitranslated according to the method disclosed in WO 96/30355.

Cabotaxel

^{1 H NMR (400 MHz, CDCl} 3) δ 8.09 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.35-7.30 (m, 5H), 6.21 (t, J = 8.6 Hz, 1H), 5.63 (d, J = 7.2 Hz, 1H), 5.45 , 4.97 (d, J = 8.4 Hz, 1H), 4.97 (d, J = 2H), 3.45 (s, 3H), 3.30 (s, 3H), 2.73-2.66 (m, ), 1.87 (s, 3H), 1.83-1.76 (m, 1 H), 1.71 (s, 3H), 1.36 (s, 3 H);

¹³ C NMR (75 MHz, CDCl ₃ ) δ 204.94, 172.69, 170.43, 166.97, 155.30, 138.67, 138.36, 135.61, 133.64, 129.18, 128.81, 128.64, 128.05, 126.83, 84.09, 82.64, 81.75, 80.75, 80.23, , 77.23, 74.52, 73.69, 72.56, 57.34, 57.04, 56.91, 56.18, 47.39, 43.29, 35.22, 32.12, 28.21, 26.83, 22.69, 20.68, 14.64, 10.34;

LRMS (ESI) m / z 858.7 (M + Na) < ^{+ &}

Example  One: Amorphous Cabot of Texel  Produce

1-1: Cabbage Tackle 2 g of a white solid was dissolved in a mixed solvent of dichloromethane / methanol (100/2 mL) and then filtered. The resulting solution was concentrated in vacuo at about < RTI ID = 0.0 > 40 C < / RTI > and the concentrate was vacuum dried at about 60 C for about 40 hours to quantitatively yield the desired compound as a white solid. The melting point of the resultant by differential scanning calorimetry (DSC) was about 131 ° C.

1-2: Cavajetaxel 10 g of white solid was added to 50 mL of methanol, refluxed for about 30 minutes to dissolve, and then filtered. The resulting filtrate was concentrated in vacuo at about 40 캜 to obtain an oily phase concentrate. The concentrate was slurried at room temperature for about 2 hours while 500 mL of hexane was added. The resulting precipitate was filtered and vacuum-dried at about 60 캜 for about 40 hours to obtain a target compound in a white solid quantitatively. The melting point of the resultant by differential scanning calorimetry (DSC) was about 131 ° C.

1-3: Cabbage bathtackel White solid (10 g) was added to methanol (50 mL), refluxed for about 30 minutes to dissolve and then filtered. The resulting filtrate was concentrated in vacuo at about 40 캜 to obtain an oily phase concentrate. The concentrate was slurried at room temperature for about 2 hours while 600 mL of heptane was added. The resulting precipitate was filtered and vacuum-dried at about 60 캜 for about 40 hours to obtain a target compound in a white solid quantitatively. The melting point of the resultant by differential scanning calorimetry (DSC) was about 131 ° C.

1-4: Cabbage bathtackel White solid (10 g) was added to methanol (50 mL), refluxed for about 30 minutes to dissolve and then filtered. The obtained filtrate was allowed to stand at about -20 DEG C for about 24 hours to form a precipitate, which was then filtered and vacuum-dried at about 60 DEG C for about 40 hours to obtain about 1.5 g of the target compound as a white solid. The melting point of the resultant by differential scanning calorimetry (DSC) was about 131 ° C.

1-5: Cabbage Takkel 10 g of white solid was dissolved in 50 mL of dichloromethane and filtered. The obtained solution was passed through a spray dryer to form a precipitate, which was then vacuum-dried at about 60 ° C for about 40 hours to obtain 8.2 g of the target compound as a white solid. The melting point by differential scanning calorimetry (DSC) was about 131 ° C.

Example  2: Cabotaxel  Preparation of anhydrous crystals

2-1: 2 g of amorphous carbajetaxel obtained in the same manner as in Example 1-1 was completely dissolved in 10 mL of dichloromethane at room temperature. 50 mL of hexane was added dropwise thereto to generate crystals. The resulting crystals were slurried at about 25 DEG C for about 2 hours and then filtered. The obtained crystals were vacuum-dried at about 60 DEG C for about 40 hours to obtain 1.8 g of anhydrous castaxate crystals (moisture: 0.2 wt% or less). The melting point of the crystals obtained by differential scanning calorimetry (DSC) was about 153 ° C.

2-2: 2 g of the amorphous carbajetaxel obtained in the same manner as in Example 1-1 was completely dissolved in 10 mL of dichloromethane at room temperature. 100 mL of heptane was added dropwise thereto to generate crystals. The resulting crystals were slurried at about 25 DEG C for about 3 hours and then filtered. The obtained crystals were vacuum-dried at about 60 캜 for about 40 hours to obtain 1.9 g of anhydrous castaxate crystals (moisture content: 0.2% by weight or less). The melting point of the crystals obtained by differential scanning calorimetry (DSC) was about 153 ° C.

2-3: 2 g of amorphous carbajetaxel obtained in the same manner as in Example 1-1 was completely dissolved in 12 mL of acetone at room temperature. 40 mL of hexane was added dropwise thereto to generate crystals. The resulting crystals were slurried at about 25 DEG C for about 2 hours and then filtered. The obtained crystals were vacuum-dried at about 50 DEG C for about 50 hours to obtain 1.8 g of anhydrous castazate anhydrous crystals (moisture content: 0.2% by weight or less). The melting point of the crystals obtained by differential scanning calorimetry (DSC) was about 153 ° C.

2-4: 2 g of amorphous carbapatite obtained in the same manner as in Example 1-1 was completely dissolved in 12 mL of acetone at room temperature. 60 mL of heptane was added dropwise thereto to generate crystals. The resulting crystals were slurried at about 25 DEG C for about 2 hours and then filtered. The obtained crystals were vacuum-dried at about 50 DEG C for about 50 hours to obtain 1.8 g of anhydrous castazate anhydrous crystals (moisture content: 0.2% by weight or less). The melting point of the crystals obtained by differential scanning calorimetry (DSC) was about 153 ° C.

Example  3: Cabot of Texel  Preparation of ethyl acetate solvate

3-1: 3 g of cabbage tablet obtained in the same manner as in Example 1 or 2 was put into 60 mL of ethyl acetate, refluxed for about 30 minutes to dissolve, and then filtered. The resulting filtrate was stirred at room temperature for about 1 hour, and the resulting precipitate was filtered and vacuum-dried at about 40 ° C for about 2 hours to obtain 1.8 g of a target compound as a white solid (water content: 0.2% by weight or less, ethyl acetate About 9.4 wt%). The melting point of the solid obtained by differential scanning calorimetry (DSC) was about 154 ° C.

3-2: 10 g of cabbage tablet obtained by the same method as in Example 1 or 2 was put into 400 mL of ethyl acetate and refluxed for about 30 minutes to dissolve. 400 mL of hexane was added dropwise thereto, and the mixture was stirred at room temperature for about 2 hours to produce crystals. The obtained crystals were filtered and vacuum-dried at about 40 ° C for about 4 hours to obtain 10.5 g of ethyl acetate solvate crystals of carbapataxel (water content: 0.2% by weight or less, ethyl acetate content by GC: about 9.3% by weight). The melting point of the obtained crystal by differential scanning calorimetry (DSC) was about 154 ° C.

3-3: 10 g of the cabbage bath obtained in the same manner as in Example 1 or 2 was put into 400 mL of ethyl acetate and refluxed for about 30 minutes to dissolve. 600 mL of heptane was added dropwise thereto, and the mixture was stirred at room temperature for about 2 hours to produce crystals. The resulting crystals were filtered and vacuum-dried at about 40 ° C for 6 hours to obtain 10.7 g of an ethyl acetate solvate crystal of carbazataxel (moisture content 0.2% by weight or less, ethyl acetate content by GC: about 9.4% by weight). The melting point of the obtained crystal by differential scanning calorimetry (DSC) was about 154 ° C.

While maintaining the amorphous (Example 1-1), anhydrous crystalline form (Example 2-1) and solvate crystalline form (Example 3-2) of the prepared cabbage tablet at 60 ° C for 10 weeks, HPLC purity Change was checked. The results are shown in Table 1 below.

In addition, the ethyl acetate solvate crystal was allowed to stand in a chamber at 25 ° C and a relative humidity of 60% for 7 days, and moisture content after the initial and after standing was measured. As a result of the measurement, initial water content was 0.2% by weight or less, and after 7 days, water content was also 0.2% by weight or less. Also no change was detected on PXRD after 7 days of incubation.

Claims (10)

(1) dissolving cabbage bath in dichloromethane or a mixed solvent of dichloromethane and methanol,
(2) concentrating the resulting solution of step (1), and
(3) A method for producing amorphous cabbage tablet, comprising the step of obtaining a carbazate tablet in a solid form from the resulting concentrate of step (2). (1) dissolving cabbage bath in dichloromethane or a mixed solvent of dichloromethane and methanol, and
(2) A method for producing amorphous cashew tablets, comprising the step of obtaining a cashew tabscell from the resultant solution of step (1) in the form of a solid. (1) dissolving cabbage bath in a solvent selected from dichloromethane, acetone and mixtures thereof, and
(2) adding crystals to the resulting solution of step (1) by adding hexane or heptane. 8. The process according to claim 7 wherein the 2-theta values on the powder X-ray diffraction (PXRD) spectrum are 7.2, 8.0, 8.9, 9.7, 10.2, 11.0, 11.8, 12.6, 12.8, 14.2, 15.2, 15.7, 16.2, 17.1, 17.5 , 17.9 and 18.4 ± 0.2 ° and characterized by a differential scanning calorimetry (DSC) melting point of 153 ± 0.3 ° C. delete delete delete delete delete delete

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