CN103467416A - Crystalline form of cabazitaxel and preparation method thereof - Google Patents
Crystalline form of cabazitaxel and preparation method thereof Download PDFInfo
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- CN103467416A CN103467416A CN 201310314053 CN201310314053A CN103467416A CN 103467416 A CN103467416 A CN 103467416A CN 201310314053 CN201310314053 CN 201310314053 CN 201310314053 A CN201310314053 A CN 201310314053A CN 103467416 A CN103467416 A CN 103467416A
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- cabazitaxel
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- BMQGVNUXMIRLCK-OAGWZNDDSA-N cabazitaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OC)C(=O)C1=CC=CC=C1 BMQGVNUXMIRLCK-OAGWZNDDSA-N 0.000 title claims abstract description 40
- 229960001573 cabazitaxel Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 16
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 238000010583 slow cooling Methods 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 201000010099 disease Diseases 0.000 description 11
- 239000013078 crystal Substances 0.000 description 9
- 238000002411 thermogravimetry Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 0 CC(*C(C)=O)(N)N=[U] Chemical compound CC(*C(C)=O)(N)N=[U] 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010062904 Hormone-refractory prostate cancer Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- CHVARVMIVJJZTG-JVXKREHESA-N [(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-acetyloxy-1-hydroxy-15-[(2R,3S)-2-hydroxy-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoyl]oxy-9,12-dimethoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.03,10.04,7]heptadec-13-en-2-yl] benzoate hydrate Chemical compound O.CO[C@H]1C[C@H]2OC[C@@]2(OC(C)=O)[C@H]2[C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C(C)=C([C@@H](OC)C(=O)[C@]12C)C3(C)C CHVARVMIVJJZTG-JVXKREHESA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Abstract
The invention relates to a crystalline form of cabazitaxel. The invention further relates to a preparation method for the crystalline form, a pharmaceutical composition containing the crystalline form and application of the crystalline form and the pharmaceutical composition in preparation of anti-cancer drugs.
Description
Technical field
The present invention relates to a kind of Cabazitaxel crystallized form, contain its pharmaceutical composition and preparation method thereof, belong to field of medicaments.
Background technology
Cabazitaxel (Cabazitaxel) is bearing taxanes, chemistry (2R by name, 3S)-3-tert-butoxycarbonyl amino-PLA 4-acetoxyl group-2 α-benzoyloxy-5 β, 20-epoxy-1-hydroxyl-7 β, 10 β-dimethoxy-9-oxo-Japanese yew-11-alkene-13 α-Ji ester, during mainly being applicable to Docetaxel (advanced prostate cancer common medicine) treatment or afterwards transitivity hormone-refractory prostate cancer (mHRPC) and the leukaemic of worsening have occurred in the state of an illness.
International Application No. WO 9630355A or WO9925704 disclose Cabazitaxel the preparation method, products therefrom is not crystallization, amorphous through being characterized by.The acetone solvent compound (being called crystal form A) of WO2005028462A Cabazitaxel.WO2009115655A disclose Cabazitaxel without hydrate (crystal form B, C, D, E, F), ethanol solvate (crystal form B, D, E), ethanol/different solvate crystal formation F, monohydrate crystal form C, the dihydrate crystal C is wherein the most stable anhydrous form without hydrate D.
Summary of the invention
The invention provides a kind of Cabazitaxel crystallized form, its PXRD collection of illustrative plates has following characteristic peak:
。
Further, the PXRD collection of illustrative plates of described Cabazitaxel crystallized form has PXRD collection of illustrative plates as shown in Figure 1.
Show the water molecules that Cabazitaxel crystallized form of the present invention contains 1 molecule according to the characterization result of IR, DSC, TG.
The present invention also provides a kind of method for preparing the Cabazitaxel crystallized form, comprises the following steps: Cabazitaxel is dissolved in ethanol, then adds water, be placed in 50 ℃～60 ℃ water-baths, dissolve Slow cooling fully, standing crystallization 8-24 hour, vacuum-drying obtains crystallized form.
In some embodiments of the present invention, described ethanol is 95% ethanol.In some embodiments of the present invention, described vacuum-drying temperature is 25 ℃.
The present invention also provides a kind of pharmaceutical composition, the Cabazitaxel crystallized form of the present invention and the pharmaceutically acceptable auxiliary material that contain dose therapeutically effective.
Cabazitaxel crystallized form of the present invention or pharmaceutical composition can be used for preparing cancer therapy drug, preferably prostate cancer or leukemia.
Cabazitaxel hydrate crystallization form of the present invention, have following advantage: the noresidue solvent; Excellent chemical purity, mobility, solvability, brilliant looks or crystal habit, stability (such as storing, degrade, turn brilliant, water absorbability); Preparation technology is simple, is more suitable for industrialization.
In sum, kappa crystallized form of the present invention is convenient to the use of pharmaceutical industry.
Herein, "
crystallized form (crystallization polymorphic)" refer to and be bordering on pure crystallized form.Herein, term "
be bordering on pure" refer to the purity>=85wt% of crystallized form of the present invention, preferably>=95wt%, more preferably>=99wt%.
, for the characteristic diffraction peak that characterizes crystallized form, there is circulation ratio herein, and its diffraction angle 2-theta (particular value ± 0.2 °) in certain limit of error.
Herein, " X-ray powder diffraction (PXRD) collection of illustrative plates as shown in Figure 1 " refers to that described PXRD collection of illustrative plates has the characteristic diffraction peak shown in accompanying drawing 1, the peak heights of these characteristic diffraction peaks (with respect to highest peak, relative height is 100%)>10% wherein, preferably>20%.
Crystallisation process of the present invention can also adopt or not adopt suitable crystal seed to realize.Crystallisation process in the present invention is affected by the running balance of different crystallized forms under specified conditions.Therefore, those skilled in the art will recognize that the acquisition of target crystallized form depends on kinetics and the Thermodynamics of crystallisation process.(solvent systems, temperature, pressure and compound concentration) under certain condition, a certain crystallized form may more stable than another kind (or being more stable than other any crystalline forms).Yet on thermodynamics, Asia-Pacific is stablized polymorphic and may be had advantage at dynamics.These crystallized forms are affected by the factor beyond kinetics also may, as time, Impurity Distribution, disturbance, existence or there is not crystal seed.
Herein, "
dose therapeutically effective" refer to the consumption of medicinal compound, when using the experimenter with treatment disease or at least one disease, disorder and clinical symptom thereof, be enough to affect the consumption of the treatment of this disease, disorder and symptom thereof.Should " dose therapeutically effective " along with compound, disease, disorder and symptom thereof, disease, disorder and severity of symptom thereof, the difference of patient age and body weight and changing.Those skilled in the art can realize determining suitable consumption by routine.In the situation that combination therapy, "
dose therapeutically effective" be disease, disorder or disease to be treated to total consumption of effective coupling activeconstituents.
Pharmaceutical composition of the present invention can be made target formulation by ordinary method in pharmaceutical field.For example, can, by activeconstituents and one or more mixed with excipients, make mixture arrive the target prescription.Herein, term "
pharmaceutically acceptable auxiliary material" refer to and be applicable to pharmaceutical preparation, the conventional auxiliary material used pharmaceutically.Preferably, the auxiliary material that is suitable for drug target preparation and route of administration.
Herein, term "
pharmaceutically acceptable" refer to the component that is applicable to people and/or other animals, and it is without excessive adverse side effect (as toxicity, irritant reaction, anaphylaxis etc.).
Herein, term "
disease" or "
disorderly" refer to any disease, discomfort, disease, symptom or disease.
The accompanying drawing explanation
X-ray powder diffraction (PXRD) collection of illustrative plates that Fig. 1 is Cabazitaxel hydrate crystallization form in the present invention.
Fig. 1-continue PXRD spectrum data for Cabazitaxel hydrate crystallization form in the present invention.
Infrared absorption (IR) collection of illustrative plates that Fig. 2 is Cabazitaxel hydrate crystallization form in the present invention.
Means of differential scanning calorimetry (DSC) collection of illustrative plates that Fig. 3 is Cabazitaxel hydrate crystallization form in the present invention.
Thermogravimetric analysis (TG) collection of illustrative plates that Fig. 4 is Cabazitaxel hydrate crystallization form in the present invention.
Specific embodiments
Those skilled in the art further explain and illustrate the present invention below by embodiment, so that can better understand the present invention.
Cabazitaxel sample related in the present invention can as required, prepare with reference to prior art.For example, with reference to the CN102417491A preparation, obtain the Cabazitaxel sample used in the embodiment of the present invention.
By 0.1g Cabazitaxel sample dissolution in 2.0mL95% ethanol, add again 1.0mL water, be placed in 50 ℃ of water-baths, sample is dissolved fully, slowly cool to room temperature, standing 24 hours crystallizatioies, the solid that collection is obtained is placed in 25 ° of C vacuum-dryings through 12 hours dryings, obtain Cabazitaxel crystallinity form, yield 81%.
By 0.2g Cabazitaxel sample dissolution in 5.0mL95% ethanol, add again 5.0mL water, be placed in 60 ℃ of water-baths, sample is dissolved fully, slowly cool to room temperature, standing 8 hours crystallizatioies, the solid that collection is obtained is placed in 25 ° of C vacuum-dryings and was drying to obtain through 2 hours, obtain Cabazitaxel crystallinity form, yield 75%.
By 0.5g Cabazitaxel sample dissolution in 10.0mL ethanol, add again 8.0mL water, be placed in 60 ℃ of water-baths, sample is dissolved fully, slowly cool to room temperature, standing 12 hours crystallizatioies, the solid that collection is obtained is placed in 25 ° of C vacuum-dryings and was drying to obtain through 6 hours, obtain Cabazitaxel crystallinity form, yield 80%.
Cabazitaxel crystallized form prepared by embodiment 1-3 carries out the experiment of X-ray powder diffraction.Detecting instrument: Japanese RigakuD/max-2550 powder x-ray diffraction: CuK α radiation, graphite monochromator, pipe is pressed 40kV, pipe stream 150mA, 2 3～80 ° of θ sweep limits, 8 °/minutes of sweep velocitys, 0.02 ° of step-length, divergent slit DS=1 °, receive slit RS=0.15mm, anti-scatter slit SS=1 °.It all has identical X-ray powder diffraction, sees accompanying drawing 1.
Cabazitaxel crystallized form of the present invention is carried out to infrared absorption (IR) spectroscopic analysis experiment.Its IR spectrum has characteristic peak at wavelength 3497,3364,3070,3026,2979,2939,2897,2828,2160,1975,1752,1710,1644,1602,1510,1498,1451,1412,1391,1374,1365,1348,1315,1266,1244,1197,1173,1161,1104,1094,1069,1049,1024,994,980,950,924,913,898,885,854,844,830,798,779,769,757,746,733,710,705,684cm-1 place, and deviation is ± 2cm-1.
Cabazitaxel crystallized form of the present invention is carried out to differential scanning calorimetric analysis (DSC) experiment.Accompanying drawing 3 is shown in by its collection of illustrative plates, and there are 2 endotherm(ic)peaks in its DSC collection of illustrative plates (temperature rise rate is 10 ° of C of per minute) at 154 ° of C ± 3 ° C and ° C place, 156 ° of C ± 3 respectively.
Cabazitaxel crystallized form of the present invention is carried out to thermogravimetric analysis (TG) experiment, and accompanying drawing 4 is shown in by its collection of illustrative plates.There is 1 weightless step in its TG collection of illustrative plates (temperature rise rate is 5 ° of C of per minute) at 150 ° of C temperature places, and weightless ratio is 2% ± 1%, is 1 molecular water.
Cabazitaxel monohydrate of the present invention and existing several crystallized forms are carried out to following estimation of stability test: place respectively the 30d sampling under 40 ℃ of conditions of temperature, measure the PXRD collection of illustrative plates.And adopt high performance liquid chromatography (HPLC) and vapor-phase chromatography (GC) to detect respectively foreign matter content (0d, 30d) and the dissolvent residual (0d) of sample.It the results are shown in Table 1.
Table 1
Claims (8)
1. a Cabazitaxel crystallized form, is characterized in that, its PXRD collection of illustrative plates has following characteristic peak:
。
2. Cabazitaxel crystallized form according to claim 1, is characterized in that, its PXRD collection of illustrative plates has PXRD collection of illustrative plates as shown in Figure 1.
3. a method for preparing Cabazitaxel crystallized form claimed in claim 1, is characterized in that, Cabazitaxel is dissolved in ethanol, add again water, be placed in 50 ℃～60 ℃ water-baths, dissolve fully, Slow cooling, standing crystallization 8-24 hour, vacuum-drying obtains crystallized form.
4. method according to claim 3, is characterized in that, described ethanol is 95% ethanol.
5. according to the described method of claim 3 or 4, it is characterized in that, described vacuum-drying temperature is 25 ℃.
6. a pharmaceutical composition, the Cabazitaxel crystallized form claimed in claim 1 and the pharmaceutically acceptable auxiliary material that contain dose therapeutically effective.
7. Cabazitaxel crystallized form claimed in claim 1 or the application of pharmaceutical composition claimed in claim 6 in preparing cancer therapy drug.
8. application according to claim 7, wherein, described cancer is selected from prostate cancer or leukemia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201310314053 CN103467416A (en) | 2013-07-24 | 2013-07-24 | Crystalline form of cabazitaxel and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201310314053 CN103467416A (en) | 2013-07-24 | 2013-07-24 | Crystalline form of cabazitaxel and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105461664A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Cabazitaxel N5 crystal form substance, and preparation method, composition and use thereof |
-
2013
- 2013-07-24 CN CN 201310314053 patent/CN103467416A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN105461664A (en) * | 2014-08-21 | 2016-04-06 | 中国医学科学院药物研究所 | Cabazitaxel N5 crystal form substance, and preparation method, composition and use thereof |
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Application publication date: 20131225 |