CN103044364B - Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof - Google Patents
Amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof Download PDFInfo
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Abstract
Crystal formation that the present invention relates to Cabazitaxel and preparation method thereof field, particularly amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.The DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.The amorphous crystalline substance of Cabazitaxel provided by the invention is the crystallized form that Cabazitaxel is new, has satisfactory stability; This preparation method simplifies operation steps, does not need specific installation, and production cost is low, is applicable to suitability for industrialized production.
Description
Technical field
Crystal formation that the present invention relates to Cabazitaxel and preparation method thereof field, particularly amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.
Background technology
Prostate cancer is a kind of elderly men disease occurred frequently, and in western countries, prostate cancer is the second largest malignant tumour of the male sex, is only second to lung cancer.According to statistics, calendar year 2001 whole world new discovery prostate cancer 198100 example, dead 31500 examples.In recent years, in China, sickness rate also rises year by year, has been classified as the 3rd of urologic neoplasms, and age of onset also rejuvenation increasingly.
Cabazitaxel (Cabazitaxel) is the Second line Drug of the treatment prostate cancer researched and developed by French Sanofi-Aventis company, in June, 2010 in U.S.'s approval listing, it is a kind of molecular design taxanes micromolecular compound, chemistry 4-acetoxyl group-2 α-benzoyloxy-5 β by name, 20-epoxy-1-hydroxyl-7 β, (the 2R of 10 β-dimethoxy-9-oxo-11-Japanese yew alkene-13 α-Ji alcohol, 3S)-3-tertbutyloxycarbonylamino-PLA ester, its structural formula is such as formula shown in I.
Formula I
The mechanism of anticancer action of Cabazitaxel is similar to docetaxel, all belongs to anti-microtubule class medicine.Cabazitaxel by with tubulin binding, promote that tubulin is assembled into stable microtubule, suppress microtubule to disintegrate, and then the performance of T suppression cell mitotic division and inerphosei cells function.Cabazitaxel is for advanced prostate cancer patients that is invalid to docetaxel, aggravation, Cabazitaxel injection liquid and prednisone drug combination, be used for the treatment of transitivity hormone-refractory prostate cancer (mHRPC) patient previously accepted containing docetaxel Regimen Chemotherapy.
There is polymorphism in Cabazitaxel, polymorphism refers to that same compound is by controlling its different formation condition, two or more molecule space arrangement mode can be formed, thus produce the phenomenon of different solid crystals, the different crystal forms of same compound, its chemical constitution is identical, but microcosmic crystalline structure is different, thus causes them to there are differences in mode of appearance, physico-chemical property and biological activity.Polymorphism directly affects the preparation processing performance of medicine, and can affect the stability of medicine, solubleness and bioavailability, and then has influence on the quality of medicine, security, validity and application thereof.Therefore, in drug research and development, the polymorphic problem of medicine should be considered comprehensively.
At present, Cabazitaxel is known exists multiple crystal formation, and patent WO2005/028462 determines and characterizes Cabazitaxel crystal form A, i.e. the acetone solvate form of Cabazitaxel; Patent WO2009/115655 determines and characterizes the anhydrate form B of Cabazitaxel, C, D, E, F, ethanolate Form B, D, E, ethanol/water different solvate F, monohydrate form C and dihydrate form C.But the amorphous crystalline substance of Cabazitaxel have not been reported.
Summary of the invention
In view of this, the invention provides amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.The amorphous crystalline substance of this Cabazitaxel is the crystallized form that Cabazitaxel is new, has satisfactory stability; This preparation method simplifies operation steps, does not need specific installation, and production cost is low, is applicable to suitability for industrialized production.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides the amorphous crystalline substance of a kind of Cabazitaxel, dsc (DSC) collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.
As preferably, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel has exothermic peak between 219 ~ 256 DEG C.
As preferably, infrared spectra (IR) collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is at wave number σ ± 2cm
-1there is peak position, and σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709.
As preferably, x-ray powder diffraction (XRPD) collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is not containing identifiable diffraction peak shape.
Present invention also offers the preparation method of the amorphous crystalline substance of a kind of Cabazitaxel, crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
As preferably, hydrocarbon is selected from C
1-5chloroparaffin.
As preferably, alcohol is selected from C
1-4alcohol.
As preferably, ester is selected from ethyl acetate, ethyl formate, diethyl malonate.
As preferably, ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF).
As preferably, ketone is selected from acetone, butanone.
Preferably, organic solvent is selected from ethanol, methylene dichloride, acetone.
As preferably, in g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100.
As preferably, concentrated temperature is 20 ~ 80 DEG C.
Preferably, concentrated temperature is 40 ~ 60 DEG C.
As preferably, concentrate at reduced pressure conditions.
As preferably, dry temperature is 30 ~ 100 DEG C.
Preferably, dry temperature is 50 ~ 70 DEG C.
More preferably, dry temperature is 50 ~ 60 DEG C.
As preferably, carry out drying at reduced pressure conditions.
As preferably, the dry time is 2 ~ 12h.
As preferably, solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, the moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
Present invention also offers the amorphous crystalline substance of a kind of Cabazitaxel obtained by above-mentioned preparation method;
The preparation method of the amorphous crystalline substance of this Cabazitaxel is: crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
As preferably, hydrocarbon is selected from C
1-5chloroparaffin.
As preferably, alcohol is selected from C
1-4alcohol.
As preferably, ester is selected from ethyl acetate, ethyl formate, diethyl malonate.
As preferably, ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF).
As preferably, ketone is selected from acetone, butanone.
Preferably, organic solvent is selected from ethanol, methylene dichloride, acetone.
As preferably, in g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100.
As preferably, concentrated temperature is 20 ~ 80 DEG C.
Preferably, concentrated temperature is 40 ~ 60 DEG C.
As preferably, concentrate at reduced pressure conditions.
As preferably, dry temperature is 30 ~ 100 DEG C.
Preferably, dry temperature is 50 ~ 70 DEG C.
More preferably, dry temperature is 50 ~ 60 DEG C.
As preferably, carry out drying at reduced pressure conditions.
As preferably, the dry time is 2 ~ 12h.
As preferably, solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, the moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
Present invention also offers a kind of pharmaceutical preparation, be made up of the amorphous crystalline substance of Cabazitaxel and pharmaceutically acceptable auxiliary material;
The DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.
Preferably, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel has exothermic peak between 219 ~ 256 DEG C.
As preferably, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is at wave number σ ± 2cm
-1there is peak position, and σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709.
As preferably, the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is not containing identifiable diffraction peak shape.
The amorphous crystalline substance of this Cabazitaxel is obtained by following preparation method:
Crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
As preferably, hydrocarbon is selected from C
1-5chloroparaffin.
As preferably, alcohol is selected from C
1-4alcohol.
As preferably, ester is selected from ethyl acetate, ethyl formate, diethyl malonate.
As preferably, ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF).
As preferably, ketone is selected from acetone, butanone.
Preferably, organic solvent is selected from ethanol, methylene dichloride, acetone.
As preferably, in g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100.
As preferably, concentrated temperature is 20 ~ 80 DEG C.
Preferably, concentrated temperature is 40 ~ 60 DEG C.
As preferably, concentrate at reduced pressure conditions.
As preferably, dry temperature is 30 ~ 100 DEG C.
Preferably, dry temperature is 50 ~ 70 DEG C.
More preferably, dry temperature is 50 ~ 60 DEG C.
As preferably, carry out drying at reduced pressure conditions.
As preferably, the dry time is 2 ~ 12h.
As preferably, solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
As preferably, when solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
As preferably, the moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
As preferably, the formulation of pharmaceutical preparation is tablet, pill, powder, granule, capsule or injection.
The invention provides amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.The DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.The amorphous crystalline substance of Cabazitaxel provided by the invention is the crystallized form that Cabazitaxel is new, has satisfactory stability; The Cabazitaxel of crystal type only need be dissolved in organic solvent by this preparation method, through concentrate drying, can obtain Residual organic solvent and the low amorphous crystalline substance of Cabazitaxel of water content, simplify operation steps, do not need specific installation, production cost is low, is applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 shows the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 14 provides;
Fig. 2 shows the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 14 provides;
Fig. 3 shows the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 14 provides;
Fig. 4 shows the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 15 provides;
Fig. 5 shows the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 15 provides;
Fig. 6 shows the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 15 provides;
Fig. 7 shows the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 16 provides;
Fig. 8 shows the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 16 provides;
Fig. 9 shows the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that the embodiment of the present invention 16 provides.
Embodiment
The invention discloses amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof, those skilled in the art can use for reference present disclosure, and suitable improving technique parameter realizes.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope methods and applications as herein described are changed or suitably change with combination, realize and apply the technology of the present invention.
The invention provides the amorphous crystalline substance of a kind of Cabazitaxel, the DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.
Cabazitaxel can exist in different physical forms, and the feature of polymorphism is everlasting in medicine and can be existed with two or more crystalline phases, in different crystalline phase lattice the arrangement of molecule and/or conformation different.The different crystal forms of Cabazitaxel, its chemical constitution is identical, but microcosmic crystalline structure is different, thus Cabazitaxel is caused to there are differences in mode of appearance, physico-chemical property and biological activity, these characteristics directly affect its processing characteristics, and the stability of Cabazitaxel, solubleness and bioavailability can be affected, and then have influence on the quality of Cabazitaxel, security, validity and application thereof.The amorphous crystalline substance of Cabazitaxel, by the molecular composition of lack of alignment, does not have unique lattice.Amorphous crystalline substance is generally more soluble than other crystal formations, causes bioavailability faster.
There is no there is no endothermic melting peak in peak or DSC figure in XRPD figure, the existence of amorphous substance can be shown.
In embodiments more provided by the invention, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel has exothermic peak between 219 ~ 256 DEG C.
In embodiments more provided by the invention, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is at wave number σ ± 2cm
-1there is peak position, and σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709.
In embodiments more provided by the invention, the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is not containing identifiable diffraction peak shape.
Present invention also offers the preparation method of the amorphous crystalline substance of a kind of Cabazitaxel, crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
In embodiments more provided by the invention, hydrocarbon is selected from C
1-5chloroparaffin.
In other embodiments provided by the invention, alcohol is selected from C
1-4alcohol.
In other embodiments provided by the invention, ester is selected from ethyl acetate, ethyl formate, diethyl malonate.
In other embodiments provided by the invention, ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF).
In other embodiments provided by the invention, ketone is selected from acetone, butanone.
In order to ensure organic solvent evaporation speed and lower Determination of Residual Organic Solvents faster, in other embodiments provided by the invention, organic solvent is selected from ethanol, methylene dichloride, acetone.
In embodiments more provided by the invention, in g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100.
In order to be removed from solid by organic solvent, concentrate solution heating in embodiments more provided by the invention, concentrated temperature is 20 ~ 80 DEG C.
When concentrated temperature is 40 ~ 60 DEG C, concentrated effect is better.
At reduced pressure conditions, the vaporator rate of organic solvent is high relative to the vaporator rate under condition of normal pressure.In order to ensure higher vaporator rate, in embodiments more provided by the invention, organic solvent concentrates at reduced pressure conditions.
In order to both ensure the quality of amorphous crystalline substance, ensure again vaporator rate faster, in embodiments more provided by the invention, dry temperature is 30 ~ 100 DEG C.
In other embodiments provided by the invention, when dry temperature is 50 ~ 70 DEG C, dry effect is better.
In other embodiments provided by the invention, when dry temperature is 50 ~ 60 DEG C, dry effect reaches splendid.
In embodiments more provided by the invention, the amorphous crystalline substance of Cabazitaxel carries out drying at reduced pressure conditions.
In embodiments more provided by the invention, the dry time is 2 ~ 12h.
In embodiments more provided by the invention, solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
In other embodiments provided by the invention, solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
In other embodiments provided by the invention, when solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
In other embodiments provided by the invention, when solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm.
In other embodiments provided by the invention, when solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm.
In embodiments more provided by the invention, the moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
Present invention also offers the amorphous crystalline substance of a kind of Cabazitaxel obtained by above-mentioned preparation method; The preparation method of the amorphous crystalline substance of this Cabazitaxel is: crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
In embodiments more provided by the invention, in preparation method provided by the invention, hydrocarbon is selected from C
1-5chloroparaffin; Alcohol is selected from C
1-4alcohol; Ester is selected from ethyl acetate, ethyl formate, diethyl malonate; Ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); Ketone is selected from acetone, butanone; In order to ensure organic solvent evaporation speed and lower Determination of Residual Organic Solvents faster, organic solvent is selected from ethanol, methylene dichloride, acetone; In g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100; In order to be removed from solid by organic solvent, concentrate solution heating, concentrated temperature is 20 ~ 80 DEG C; When concentrated temperature is 40 ~ 60 DEG C, concentrated effect is better; At reduced pressure conditions, the vaporator rate of organic solvent is high relative to the vaporator rate under condition of normal pressure, and in order to ensure higher vaporator rate, organic solvent concentrates at reduced pressure conditions; In order to both ensure the quality of amorphous crystalline substance, ensure again vaporator rate faster, dry temperature is 30 ~ 100 DEG C; When dry temperature is 50 ~ 70 DEG C, dry effect is better; When dry temperature is 50 ~ 60 DEG C, dry effect reaches splendid; The amorphous crystalline substance of Cabazitaxel carries out drying at reduced pressure conditions; The dry time is 2 ~ 12h; Solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm; Solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm; The moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
Present invention also offers a kind of pharmaceutical preparation, be made up of the amorphous crystalline substance of Cabazitaxel and pharmaceutically acceptable auxiliary material;
In embodiments more provided by the invention, the DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.
In other embodiments provided by the invention, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel has exothermic peak between 219 ~ 256 DEG C.
In embodiments more provided by the invention, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is at wave number σ ± 2cm
-1there is peak position, and σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709.
In embodiments more provided by the invention, the XRPD collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel is not containing identifiable diffraction peak shape.
In other embodiments provided by the invention, the amorphous crystalline substance of this Cabazitaxel is obtained by following preparation method:
Crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product;
Crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel;
Organic solvent is selected from hydrocarbon, alcohol, ester, ether, ketone.
In embodiments more provided by the invention, in the preparation method of Cabazitaxel provided by the invention, hydrocarbon is selected from C
1-5chloroparaffin, alcohol is selected from C
1-4alcohol, ester is selected from ethyl acetate, ethyl formate, diethyl malonate, and ether is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), and ketone is selected from acetone, butanone; In order to ensure organic solvent evaporation speed and lower Determination of Residual Organic Solvents faster, organic solvent is selected from ethanol, methylene dichloride, acetone; In g/mL, the mass volume ratio of crystallinity Cabazitaxel and organic solvent is 1 ︰ 5 ~ 100; In order to be removed from solid by organic solvent, concentrate solution heating, concentrated temperature is 20 ~ 80 DEG C, and when concentrated temperature is 40 ~ 60 DEG C, concentrated effect is better.At reduced pressure conditions, the vaporator rate of organic solvent is high relative to the vaporator rate under condition of normal pressure.In order to ensure higher vaporator rate, organic solvent concentrates at reduced pressure conditions; In order to both ensure the quality of amorphous crystalline substance, ensure again vaporator rate faster, dry temperature is 30 ~ 100 DEG C; When dry temperature is 50 ~ 70 DEG C, dry effect is better; When dry temperature is 50 ~ 60 DEG C, dry effect reaches splendid; The amorphous crystalline substance of Cabazitaxel carries out drying at reduced pressure conditions; The dry time is 2 ~ 12h; Solvent is C
1-5chloroparaffin time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm; Solvent is C
1-4alcohol time, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ester, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ether, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 5000ppm; When solvent is ketone, the organic residue of the amorphous crystalline substance of Cabazitaxel is lower than 15000ppm; The moisture content of the amorphous crystalline substance of Cabazitaxel is lower than 2%.
In embodiments more provided by the invention, the formulation of pharmaceutical preparation provided by the invention is tablet, pill, powder, granule, capsule or injection.
The invention provides amorphous crystalline substance of a kind of Cabazitaxel and preparation method thereof.The DSC collection of illustrative plates of the amorphous crystalline substance of this Cabazitaxel has exothermic peak between 210 ~ 260 DEG C.The amorphous crystalline substance of Cabazitaxel provided by the invention is the crystallized form that Cabazitaxel is new, has satisfactory stability; The Cabazitaxel of crystal type only need be dissolved in organic solvent by this preparation method, through concentrate drying, can obtain Residual organic solvent and the low amorphous crystalline substance of Cabazitaxel of water content, simplify operation steps, do not need specific installation, production cost is low, is applicable to suitability for industrialized production.
The present invention adopts XRPD method to detect the amorphous crystalline substance of Cabazitaxel provided by the invention, the plant and instrument used is RIGAKUTTRIII type X-ray powder diffractometer, condition determination and method: Cu/K-alpha1(target), 40KV-200mA(operating voltage and electric current), I(max)=2244,2 θ=5 ~ 60 degree (sweep limit), 0.005/0.06sec.(sweep velocity), λ=1.54056.
The present invention additionally uses IR method and detects the amorphous crystalline substance of Cabazitaxel provided by the invention, the instrument used is BRUKERTENSOR27 Fourier transform mid-infrared light spectrometer (German Brooker company), measuring method adopts KBr pressed disc method, spectral range 400cm
-1~ 4000cm
-1, resolving power is 4cm
-1.
The present invention additionally uses DSC method and detects the amorphous crystalline substance of Cabazitaxel provided by the invention.
The bulk drug used in amorphous crystalline substance of Cabazitaxel provided by the invention and preparation method thereof and reagent all can be buied by market.
Below in conjunction with embodiment, set forth the present invention further:
The preparation of the amorphous crystalline substance of embodiment 1 Cabazitaxel
The crystallization of 5g Cabazitaxel anhydride is added stirring and dissolving in 75mL ethanol, and 50 DEG C are concentrated into dry, obtain Cabazitaxel powder, by Cabazitaxel powder 60 DEG C, under reduced pressure, dry 12h, obtains the amorphous crystalline substance of 4.9g Cabazitaxel.HPLC detects purity >=99.87%, and it is 1608ppm that GC detects alcohol residue, and moisture is 0.9%.
The preparation of the amorphous crystalline substance of embodiment 2 Cabazitaxel
After 10g Cabazitaxel crystal of hydrate is dissolved with 100mL methylene dichloride, be concentrated into dry under 30 DEG C of conditions, obtain Cabazitaxel powder, by the vacuum-drying under temperature 50 ~ 60 DEG C of conditions of Cabazitaxel powder, obtain the amorphous crystalline substance of 9.9g Cabazitaxel.HPLC detects purity >=99.84%, and GC detects methylene dichloride and remains as 13080ppm, and moisture is 0.5%.
The preparation of the amorphous crystalline substance of embodiment 3 Cabazitaxel
By 10g Cabazitaxel solvate crystal with after 250mL acetone solution, be concentrated into dry under 40 DEG C of conditions, obtain Cabazitaxel powder, by the vacuum-drying under temperature 50 ~ 60 DEG C of conditions of Cabazitaxel powder, obtain the amorphous crystalline substance of 9.9g Cabazitaxel.HPLC detects purity >=99.84%, and it is 8562ppm that GC detects acetone residue, and moisture is 0.6%.
The preparation of the amorphous crystalline substance of embodiment 4 Cabazitaxel
By the crystallization of 20g Cabazitaxel anhydride with after 100mL acetic acid ethyl dissolution, be concentrated into dry under 80 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 6h under temperature 100 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.82%, and GC detects ethyl acetate and remains as 3100ppm, and moisture is 0.8%.
The preparation of the amorphous crystalline substance of embodiment 5 Cabazitaxel
By the crystal of hydrate of 5g Cabazitaxel with after 500mL ether dissolution, be concentrated into dry under 20 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 9h under temperature 30 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.78%, and GC detects ether and remains as 1600ppm, and moisture is 0.4%.
The preparation of the amorphous crystalline substance of embodiment 6 Cabazitaxel
After the solvate crystal of 5g Cabazitaxel is dissolved with 250mL butanone, be concentrated into dry under 60 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 11h under temperature 70 C condition, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.86%, and GC detects butanone and remains as 8200ppm, and moisture is 0.6%.
The preparation of the amorphous crystalline substance of embodiment 7 Cabazitaxel
After 5g Cabazitaxel crystal of hydrate is dissolved with 100mL methyl-formiate, be concentrated into dry under 70 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 8h under temperature 80 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.83%, and GC detects methyl-formiate and remains as 2600ppm, and moisture is 0.8%.
The preparation of the amorphous crystalline substance of embodiment 8 Cabazitaxel
After the anhydride crystallization of 5g Cabazitaxel is dissolved with 100mL isopropyl ether, be concentrated into dry under 20 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 7h under temperature 30 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.84%, and GC detects isopropyl ether and remains as 2300ppm, and moisture is 0.7%.
The preparation of the amorphous crystalline substance of embodiment 9 Cabazitaxel
After the crystal of hydrate of 10g Cabazitaxel is dissolved with 300mL diethyl malonate, be concentrated into dry under 35 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 6h under temperature 45 C condition, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.84%, and GC detects diethyl malonate and remains as 3300ppm, and moisture is 0.9%.
The preparation of the amorphous crystalline substance of embodiment 10 Cabazitaxel
After the solvate crystal of 5g Cabazitaxel is dissolved with 200mL methyl tertiary butyl ether, be concentrated into dry under 45 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 4h under temperature 55 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.86%, and it is 3500ppm that GC detects methyl tertbutyl ether residue, and moisture is 1.2%.
The preparation of the amorphous crystalline substance of embodiment 11 Cabazitaxel
After the crystallization of 5g Cabazitaxel anhydride is dissolved with 400mL tetrahydrofuran (THF), be concentrated into dry under 55 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 2h under temperature 65 DEG C of conditions, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.85%, and GC detects tetrahydrofuran (THF) and remains as 1100ppm, and moisture is 1.2%.
The preparation of the amorphous crystalline substance of embodiment 12 Cabazitaxel
After 5g Cabazitaxel crystal of hydrate is dissolved with 450mL dichloropentane, be concentrated into dry under 50 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 8h under temperature 60 C condition, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.84%, and GC detects dichloropentane and remains as 1800ppm, and moisture is 0.4%.
The preparation of the amorphous crystalline substance of embodiment 13 Cabazitaxel
After 20g Cabazitaxel solvate crystal is dissolved with 100mL isopropylcarbinol, be concentrated into dry under 40 DEG C of conditions, obtain Cabazitaxel powder, by Cabazitaxel powder vacuum-drying 10h under temperature 50 C condition, obtain the amorphous crystalline substance of Cabazitaxel.HPLC detects purity >=99.78%, and GC detects isopropylcarbinol and remains as 4400ppm, and moisture is 0.6%.
The detection of the amorphous crystalline substance of embodiment 14 Cabazitaxel
The amorphous crystalline substance of Cabazitaxel that Example 1 is obtained, adopt XRPD method, IR method, DSC method to detect it, its XRPD collection of illustrative plates, IR collection of illustrative plates, DSC collection of illustrative plates are shown in Fig. 1, Fig. 2, Fig. 3 respectively.
As shown in Figure 1, the XRPD collection of illustrative plates of the amorphous crystalline substance of the Cabazitaxel that embodiment 1 provides, not containing identifiable diffraction peak shape, is defined as the amorphous crystalline substance of Cabazitaxel.
As shown in Figure 2, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that provides of embodiment 1 is at wave number σ ± 2cm
-1there is peak position, and σ is 3446.91,3421.83,3091.03,3064.03,3027.38,2981.08,2940.58,2898.14,2823.88,1721.53,1718.63,1635.69,1602.90,1584.57,1495.85,1452.45,1392.65,1368.54,1316.46,1269.20,1246.06,1225.80,1169.87,1140.93,1103.32,1072.46,1060.88,1026.16,998.20,987.59,949.01,918.15,709.83.
As shown in Figure 3, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that embodiment 1 provides has exothermic peak between 219.64 ~ 254.21 DEG C.
The detection of the amorphous crystalline substance of embodiment 15 Cabazitaxel
The amorphous crystalline substance of Cabazitaxel that Example 2 is obtained, adopt XRPD method, IR method, DSC method to detect it, its XRPD collection of illustrative plates, IR collection of illustrative plates, DSC collection of illustrative plates are shown in Fig. 4, Fig. 5, Fig. 6 respectively.
As shown in Figure 4, the XRPD collection of illustrative plates of the amorphous crystalline substance of the Cabazitaxel that embodiment 2 provides, not containing identifiable diffraction peak shape, is defined as the amorphous crystalline substance of Cabazitaxel.
As shown in Figure 5, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that provides of embodiment 2 is at wave number σ ± 2cm
-1there is peak position, and σ is 3446.91,3439.19,3091.03,3064.03,3028.34,2980.12,2940.58,2898.14,2822.92,1722.49,1635.69,1602.90,1584.57,1495.85,1452.45,1392.65,1368.54,1316.46,1270.17,1246.06,1170.83,1141.90,1103.32,1072.46,1026.16,998.20,949.01,919.11,709.83.
As shown in Figure 6, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that embodiment 2 provides has exothermic peak between 220.16 ~ 255.34 DEG C.
The detection of the amorphous crystalline substance of embodiment 16 Cabazitaxel
The amorphous crystalline substance of Cabazitaxel that Example 3 is obtained, adopt XRPD method, IR method, DSC method to detect it, its XRPD collection of illustrative plates, IR collection of illustrative plates, DSC collection of illustrative plates are shown in Fig. 7, Fig. 8, Fig. 9 respectively.
As shown in Figure 7, the XRPD collection of illustrative plates of the amorphous crystalline substance of the Cabazitaxel that embodiment 3 provides, not containing identifiable diffraction peak shape, is defined as the amorphous crystalline substance of Cabazitaxel.
As shown in Figure 8, the IR collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that provides of embodiment 3 is at wave number σ ± 2cm
-1there is peak position, and σ is 3481.63,3446.91,3422.80,3393.86,3091.03,3064.99,3027.38,2980.12,2940.58,2898.14,2822.92,1722.49,1635.69,1602.90,1585.54,1496.81,1452.45,1392.65,1368.54,1315.50,1270.17,1246.06,1225.80,1170.83,1141.90,1103.32,1072.46,1026.16,998.20,949.01,918.15,709.83.
As shown in Figure 9, the DSC collection of illustrative plates of the amorphous crystalline substance of Cabazitaxel that embodiment 3 provides has exothermic peak between 219.48 ~ 252.40 DEG C.
The amorphous crystalline substance of Cabazitaxel that Example 4 ~ 13 is obtained, adopt XRPD method, IR method, DSC method to detect it, the collection of illustrative plates of its XRPD collection of illustrative plates, IR collection of illustrative plates, DSC collection of illustrative plates and embodiment 1 ~ 3 is close, and XRPD collection of illustrative plates is not containing identifiable diffraction peak shape; IR collection of illustrative plates is at wave number σ ± 2cm
-1there is peak position, and σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709; DSC collection of illustrative plates has exothermic peak between 219 ~ 256 DEG C.
The Detection of Stability of the amorphous crystalline substance of embodiment 17 Cabazitaxel
The crystal of hydrate of the amorphous crystalline substance of the Cabazitaxel that Example 1 provides and commercially available Cabazitaxel carries out stability test, the amorphous crystalline substance of Cabazitaxel that embodiment 1 is provided and the crystal of hydrate of Cabazitaxel is uncovered respectively divides placement, be determined at the moisture content of 0 month, 3 months, 6 months, purity, maximum single foreign matter content and indicate content, test-results is in table 1.
The stability test of the amorphous crystalline substance of table 1 Cabazitaxel
The data of table 1 show, the amorphous crystalline substance of the Cabazitaxel that embodiment 1 provides has good stability.
Stability test is carried out in the amorphous crystalline substance of the Cabazitaxel that Example 2 ~ 13 provides and commercially available Cabazitaxel crystallization, and result is similar to the result of the amorphous crystalline substance of the Cabazitaxel that embodiment 1 provides, and has good stability.
The preparation of embodiment 18 Cabazitaxel tablet
The amorphous crystalline substance of Cabazitaxel prepared by Example 1 mixes with customary adjuvant, conventionally prepares Cabazitaxel tablet.
The preparation of embodiment 19 Cabazitaxel tablet
The amorphous crystalline substance of Cabazitaxel prepared by Example 2 mixes with customary adjuvant, conventionally prepares Cabazitaxel tablet.
The preparation of embodiment 20 Cabazitaxel tablet
The amorphous crystalline substance of Cabazitaxel prepared by Example 3 mixes with customary adjuvant, conventionally prepares Cabazitaxel tablet.
The preparation of embodiment 21 Cabazitaxel pill
The amorphous crystalline substance of Cabazitaxel prepared by Example 4 mixes with customary adjuvant, conventionally prepares Cabazitaxel pill.
The preparation of embodiment 22 Cabazitaxel pill
The amorphous crystalline substance of Cabazitaxel prepared by Example 5 mixes with customary adjuvant, conventionally prepares Cabazitaxel pill.
The preparation of embodiment 23 Cabazitaxel powder
The amorphous crystalline substance of Cabazitaxel prepared by Example 6 mixes with customary adjuvant, conventionally prepares Cabazitaxel powder.
The preparation of embodiment 24 Cabazitaxel powder
The amorphous crystalline substance of Cabazitaxel prepared by Example 7 mixes with customary adjuvant, conventionally prepares Cabazitaxel powder.
The preparation of embodiment 25 Cabazitaxel granule
The amorphous crystalline substance of Cabazitaxel prepared by Example 8 mixes with customary adjuvant, conventionally prepares Cabazitaxel granule.
The preparation of embodiment 26 Cabazitaxel granule
The amorphous crystalline substance of Cabazitaxel prepared by Example 9 mixes with customary adjuvant, conventionally prepares Cabazitaxel granule.
The preparation of embodiment 27 Cabazitaxel capsule
The amorphous crystalline substance of Cabazitaxel prepared by Example 10 mixes with customary adjuvant, conventionally prepares Cabazitaxel capsule.
The preparation of embodiment 28 Cabazitaxel capsule
The amorphous crystalline substance of Cabazitaxel prepared by Example 11 mixes with customary adjuvant, conventionally prepares Cabazitaxel capsule.
The preparation of embodiment 29 Cabazitaxel injection
The amorphous crystalline substance of Cabazitaxel prepared by Example 12 mixes with customary adjuvant, conventionally prepares Cabazitaxel injection.
The preparation of embodiment 30 Cabazitaxel injection
The amorphous crystalline substance of Cabazitaxel prepared by Example 13 mixes with customary adjuvant, conventionally prepares Cabazitaxel injection.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles 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 (5)
1. the amorphous crystalline substance of Cabazitaxel, is characterized in that, the DSC collection of illustrative plates of the amorphous crystalline substance of described Cabazitaxel only has exothermic peak between 219 ~ 256 DEG C;
The preparation method of the amorphous crystalline substance of described Cabazitaxel is: crystal type Cabazitaxel is dissolved in organic solvent, concentrated, dry, to obtain final product; Described crystal type Cabazitaxel is the anhydride crystallization of Cabazitaxel, the crystal of hydrate of Cabazitaxel or the solvate crystal of Cabazitaxel; Described organic solvent is alcohol; Described alcohol is selected from C
1-4alcohol; Described concentrated temperature is 40 ~ 60 DEG C.
2. the amorphous crystalline substance of Cabazitaxel according to claim 1, is characterized in that, the infrared spectrogram of the amorphous crystalline substance of described Cabazitaxel is at wave number σ ± 2cm
-1there is peak position, and described σ is 3447,3091,3064,3027,2980,2940,2898,2823,1722,1635,1602,1584,1496,1452,1392,1368,1316,1270,1246,1170,1141,1103,1072,1026,998,949,919 and 709.
3. the amorphous crystalline substance of Cabazitaxel according to claim 1, is characterized in that, in g/mL, the mass volume ratio of described crystal type Cabazitaxel and described organic solvent is 1 ︰ 5 ~ 100.
4. the amorphous crystalline substance of Cabazitaxel according to claim 1, is characterized in that, the temperature of described drying is 30 ~ 100 DEG C.
5. a pharmaceutical preparation, is characterized in that, is made up of the amorphous crystalline substance of the Cabazitaxel as described in any one of Claims 1 to 4 and pharmaceutically acceptable auxiliary material; The formulation of described pharmaceutical preparation is tablet, pill, powder or granule.
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| AU2013368947B2 (en) * | 2012-12-31 | 2016-11-24 | Shilpa Medicare Limited | Process for preparing amorphous Cabazitaxel |
| CN103601704B (en) * | 2013-11-22 | 2015-05-06 | 石家庄智恒医药科技有限公司 | Preparation method of amorphous cabazitaxel |
| CN105461665A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Cabazitaxel N6 crystal form substance, and preparation method, composition and use thereof |
| CN105367521A (en) * | 2014-08-21 | 2016-03-02 | 中国医学科学院药物研究所 | Cabazitaxel N4 crystal form substance, and preparation method, composition and use thereof |
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