CN104761492A - Crystal form of sorafenib tosylate, and preparation method thereof - Google Patents
Crystal form of sorafenib tosylate, and preparation method thereof Download PDFInfo
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- CN104761492A CN104761492A CN201410003888.4A CN201410003888A CN104761492A CN 104761492 A CN104761492 A CN 104761492A CN 201410003888 A CN201410003888 A CN 201410003888A CN 104761492 A CN104761492 A CN 104761492A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention provides a crystal form of sorafenib tosylate, and a preparation method thereof. The X-ray powder diffraction pattern of sorafenib tosylate of crystal form B has diffraction peaks when the values of 2theta are about 7.34DEG, 18.03DEG, 20.15DEG, 20.77DEG, 22.04DEG, 22.43DEG and 23.21DEG; and the X-ray powder diffraction pattern of sorafenib tosylate of crystal form C has diffraction peaks when the values of 2theta are about 7.61DEG and 13-33DEG. The sorafenib tosylate of crystal form C is prepared through reduced pressure heating of the sorafenib tosylate of crystal form B. The invention also provides a preparation method of amorphous crystals of sorafenib tosylate through reduced pressure heating of the sorafenib tosylate of crystal form B or C. The sorafenib tosylate crystals prepared in the invention have the advantages of good stability, high crystallization purity, simple preparation process, and suitableness for industrial production.
Description
Technical field
Crystal formation that the present invention relates to Sorafenib Tosylate and preparation method thereof, belongs to medical art.
Background technology
Sorafenib Tosylate has the structure shown in formula I, and chemical name is 4-{4-[3-(the chloro-3-trifluoromethyl of 4-
-phenyl)-uride]-phenoxy group }-N-picoline-2-carboxylic acid methylamine tosilate, Xarelto develops listing by Bayer and Onyx, for the cytostatic kinase inhibitor of oral small molecules, the hepatocellular carcinoma (HCC) that this medicine is used for the treatment of renal cell carcinoma (RCC) and cannot excises.
The preparation method of Sorafenib Tosylate is disclosed in CN101052619, WO2009034308, US20130005980.CN101065360 disclose Sorafenib Tosylate I, II, III 3 kind of crystal and corresponding preparation method, in order to obtain stable crystal, need high temperature or long-time stirring to turn brilliant, the degree of crystallinity of gained crystal formation is not high, is difficult to the production requirement meeting the large industry of industrialization.
The change of medicinal compound crystal formation causes compound to have different fusing points, solubleness, water absorbability, stability, biological activity etc. usually, and these are all the important factors affecting difficulty or ease, stability in storage, preparation difficulty or ease and bioavailability etc. prepared by medicine.When there is polymorphic in compound, because specific polymorphic form has specific thermodynamic property and stability, therefore, in the process of preparation, the crystal formation understanding the compound applied in each formulation is important, to ensure the medicine of process application same modality.Therefore, ensure that compound be single crystal formation or the known miscellany of some crystal formations is necessary.
When judging which kind of polymorphic form is preferred, their much character must be compared and preferred polymorphic form makes a choice based on many physical propertiess.Preferred under completely likely the difficulty or ease, stability etc. of a kind of polymorphic in some aspects as preparation are considered to critical condition.In other cases, different polymorphic form may the solubleness of Yin Genggao or excellent pharmacokinetics and preferably.
The discovery of the new polymorphic form of medicinal compound provides the chance improving medicine physical property, namely whole character of material are extended, thus the research of compound and preparation thereof can be instructed better, therefore the polymorphic form of Sorafenib Tosylate provided by the invention has commercial value in the manufacture and other application of medicine.
Summary of the invention
One aspect of the present invention provides the Type B crystal of Sorafenib Tosylate, use Cu-K α radiation, it is in X-ray powder diffraction (XRD) collection of illustrative plates, and being about 7.34 °, 18.03 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 ° places at 2 θ has diffraction peak; Typically there is diffraction peak at 7.34 °, 8.2 °, 9.25 °, 18.03 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 °, 29.6 ° places; Typically there is diffraction peak at 7.34 °, 8.2 °, 9.25 °, 13.72 °, 14.69 °, 15.29 °, 16.26 °, 17.31 °, 18.03 °, 19.55 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 °, 24.41 °, 24.64 °, 29.6 ° places further; Typically there is diffraction peak at 7.34 °, 8.2 °, 9.25 °, 10.4 °, 11.27 °, 12.25 °, 13.72 °, 14.69 °, 15.29 °, 16.26 °, 17.31 °, 18.03 °, 19.55 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 °, 24.41 °, 24.64 °, 29.6 ° places further.
Use Cu-K α radiation, as shown in Figure 1, it has following feature to the spectrogram of the typical XRD of Type B crystal:
Second aspect present invention provides a kind of C N-type waferN of Sorafenib Tosylate, it is characterized in that, use Cu-K α radiation, in X-ray powder diffraction (XRD) collection of illustrative plates, be about 7.61 ° and there is diffraction peak at 16 ° of-27 ° of places at 2 θ, be typically about 7.61 ° and there is diffraction peak at 13 ° of-33 ° of places at 2 θ.Locate as wide diffraction peak for wherein said 16 °-27 ° and 13 °-33 °.In a particular embodiment of the process of the present invention, there is X-ray powder diffraction (XRD) collection of illustrative plates shown in Fig. 2.
Third aspect present invention, provides the preparation method of above-mentioned Type B crystal, C N-type waferN and amorphous Sorafenib Tosylate.
In some embodiments, provide a kind of preparation method of Type B crystal, comprise the tetrahydrofuran solution preparing Xarelto, optionally, can add gac and filter, gained solution is lowered the temperature, and adds tosic acid or its hydrate, crystallization, is separated and obtains crystal.
Wherein, when preparing the tetrahydrofuran solution of Xarelto, the ratio (w/v, grams per milliliter) of Xarelto and tetrahydrofuran (THF) is 1:10-100, preferred 1:15-45.During the cooling of gained solution, described temperature is 10 DEG C ~-80 DEG C, preferably 0 DEG C ~-40 DEG C, more preferably-20 DEG C ~-10 DEG C; In a specific embodiment, described temperature is-15 DEG C.
When adding tosic acid, tosic acid and Xarelto mol ratio are 0.5 ~ 10:1; Preferably 1 ~ 1.5:1.In a specific embodiment, add a hydration tosic acid.During crystallization, by stirring or adding the precipitation that the conventional methods such as crystal seed promote crystal.Organic solvent (such as sherwood oil, isopropyl ether, methyl tertiary butyl ether, normal heptane or normal hexane) can be used further to wash when isolation of crystalline.In preferred embodiments, temperature when solution is cooled to crystallization all remains on 10 DEG C ~-80 DEG C, preferably 0 DEG C ~-40 DEG C, more preferably-20 DEG C ~-10 DEG C.
In some embodiments, provide the preparation method of the C N-type waferN of Sorafenib Tosylate, comprise Type B crystal drying under reduced pressure at 40 DEG C ~ 80 DEG C.In one particular embodiment, at 60 DEG C, dry under-0.09 ~-0.1Mpa.
In some embodiments, provide the preparation method of amorphous Sorafenib Tosylate, comprise the drying under reduced pressure at 80 DEG C ~ 120 DEG C by above-mentioned Type B crystal or C N-type waferN and prepare.
Fourth aspect, the invention provides the pharmaceutical composition of above-mentioned crystal.Described pharmaceutical composition also comprises one or more pharmaceutical excipients, optionally, also can comprise other therapeutic activity composition.Also can with chemotherapy, radiotherapy, these therapy Combined Preparation of surgical operation.
Described pharmaceutical composition is preferably with oral administration.Be applicable to oral pharmaceutical composition and comprise tablet, capsule, pulvis, granule, dripping pill, paste, powder, tincture etc., preferred tablet and capsule.Wherein tablet can be conventional tablet, dispersible tablet, effervescent tablet, slow releasing tablet, controlled release tablet or enteric coated tablet, and capsule can be conventional capsule, slow releasing capsule, controlled release capsule or enteric coated capsule.
Pharmaceutical composition of the present invention can use conventional pharmaceutical adjuvants well known in the art to be obtained by ordinary method.Conventional pharmaceutical excipient comprises weighting agent, absorption agent, wetting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent comprises starch, lactose, N.F,USP MANNITOL, Microcrystalline Cellulose etc.; Absorption agent comprises calcium sulfate, secondary calcium phosphate, calcium carbonate, magnesium oxide etc.; Wetting agent comprises water, ethanol etc.; Tackiness agent comprises hypromellose, polyvidone, Microcrystalline Cellulose etc.; Disintegrating agent comprises croscarmellose sodium, polyvinylpolypyrrolidone, tensio-active agent, low-substituted hydroxypropyl cellulose etc.; Lubricant comprises Magnesium Stearate, talcum powder, polyoxyethylene glycol, Stepanol MG, micropowder silica gel, talcum powder etc.Pharmaceutical excipient is also comprising toner, sweeting agent etc.
5th aspect, the invention provides above-mentioned crystal, pharmaceutical composition for the preparation for the treatment of antitumor drug in purposes.
Herein, according to Chinese Pharmacopoeia 2010 editions two annex Ⅸ F, the X-ray Powder Diffraction pattern of sample measures under the following conditions, instrument and model thereof: D/Max-RA Japan RigakuXMiniFlex II X-ray powder diffractometer; Ray: monochromatic Cu-Ka ray
scan mode: θ/2 θ, sweep limit: 0-40 ° voltage: 30Kv, electric current 15mA; Sense environmental conditions: temperature: 23.9 DEG C, humidity: 38.6%.
It should be noted that, in X-ray Powder Diffraction pattern (XRD), the diffraction spectrogram obtained by crystalline compounds is distinctive often for specific crystal formation, wherein the relative intensity of bands of a spectrum (especially at low angle) the advantage orientation effect that may produce because of the difference of crystal condition, particle diameter and other condition determination and changing.Therefore, the relative intensity of diffraction peak to for crystal formation be not distinctive, when judging whether identical with known crystal formation, should be noted that relative position instead of their relative intensity at peak.In addition, for any given crystal formation, may there is slight errors in the position at peak, and this is also known in crystallography art.Such as, because the change of temperature during analytic sample, sample move or the demarcation etc. of instrument, the position at peak can be moved, and the error at measurment of 2 θ values is about sometimes ± and 0.2 °.Therefore, when determining often kind of crystalline texture, this error should be taken into account.In XRD figure spectrum, usually represent peak position with 2 θ angles or crystal face apart from d, have simple conversion relation between the two: d=λ/2sin θ, wherein d represents crystal face distance, and λ represents the wavelength of incident X-rays, and θ is diffraction angle.For the crystal formation of the same race of same compound, the peak position that its XRD composes has similarity on the whole, and relative intensity error may be larger.Should be noted also that in the qualification of mixture, because under content, degradation factor can cause the disappearance of portion diffracts line, now, without the need to relying in high-purity sample the whole bands of a spectrum observed, even bands of a spectrum may be also distinctive to given crystal.
The crystal purity of Sorafenib Tosylate provided by the invention is high, degree of crystallinity is high, good stability, water absorbability are little, water-soluble good, good fluidity; Meanwhile, simply, solvent is cheap and easy to get for the new crystal of Sorafenib Tosylate provided by the invention and unbodied preparation method, and crystallization condition is gentle, is applicable to suitability for industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction pattern of the Sorafenib Tosylate crystal that Fig. 1 embodiment 1 prepares
The X-ray powder diffraction pattern of the Sorafenib Tosylate crystal that Fig. 2 embodiment 2 prepares
The X-ray powder diffraction pattern of the amorphous Sorafenib Tosylate that Fig. 3 embodiment 3 prepares
The X-ray powder diffraction pattern of Sorafenib Tosylate I N-type waferN of Fig. 4 embodiment 4
Fig. 5 implements the DSC figure of the Sorafenib Tosylate crystal that 2 prepare
The infrared spectrogram of the Sorafenib Tosylate crystal that Fig. 6 embodiment 2 prepares
The infrared spectrogram of the amorphous Sorafenib Tosylate that Fig. 7 embodiment 3 prepares
The infrared spectrogram of Sorafenib Tosylate I N-type waferN of Fig. 8 embodiment 4
Embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to described scope of embodiments.The reagent adopted is commercially available prod.
The preparation of embodiment 1 Sorafenib Tosylate Type B crystal
Get 10.0g Xarelto, add 200mL tetrahydrofuran (THF), stir molten clear after add 2g gac, stir 30min, filter, filtrate cools to-15 DEG C, and dropping 4.3g mono-hydration tosic acid is dissolved in the solution in 13mL tetrahydrofuran (THF), adds rear stirring and crystallizing 1 hour, filter, filter cake 100ml isopropyl ether rinsing, obtains crystal, and it has the X-ray powder diffraction figure shown in Fig. 1.
The preparation of embodiment 2 Sorafenib Tosylate C N-type waferN
The crystal that embodiment 1 prepares decompression drying 5 hours at 60 DEG C, obtains the C N-type waferN of 12.9g Sorafenib Tosylate, purity 99.9%.It has the X-ray powder diffraction figure shown in Fig. 2.
The preparation of the amorphous Sorafenib Tosylate of embodiment 3
The product of embodiment 1 or embodiment 2 decompression drying 20 hours at 80 DEG C, obtains amorphous Sorafenib Tosylate, purity 99.87%.It has the X-ray powder diffraction figure shown in Fig. 3.
The preparation (reference) of embodiment 4 Sorafenib Tosylate I crystal formation
Get 10.0g Xarelto, add 30mL dehydrated alcohol, be warmed up to 25 DEG C, dropping 4.3g mono-hydration tosic acid is dissolved in the solution in 13mL ethanol, adds rear stirring and crystallizing 1 hour, filters, filter cake 30ml dehydrated alcohol rinsing, at 60 DEG C, decompression drying 8 hours, obtains 12.7g Sorafenib Tosylate, purity 99.87%.It has the X-ray powder diffraction figure shown in Fig. 4.
The preparation of embodiment 5 Sorafenib Tosylate Type B crystal
Get 10.0Kg Xarelto, add 200L tetrahydrofuran (THF), stir molten clear after add 500g gac, stir 30min, press filtration, filtrate cools to-15 DEG C, adds 4.3Kg mono-hydration tosic acid, adds rear stirring and crystallizing 1 hour, rejection filter, filter cake 100L sherwood oil is washed, and obtains crystal, and it has the X-ray powder diffraction figure shown in Fig. 1.
The preparation of embodiment 6 Sorafenib Tosylate C N-type waferN
The crystal that embodiment 5 prepares decompression drying 8 hours at 60 DEG C, obtains the C N-type waferN of 12.5Kg Sorafenib Tosylate, yield 90.7%, purity 99.89%.It has the X-ray powder diffraction figure shown in Fig. 2.
The liquid-phase condition that embodiment 7 Sorafenib Tosylate HPLC analyzes
Detecting instrument: Thermo U3000 high performance liquid chromatograph;
Chromatographic column: Thermo Accucore XL C18 (150*4.6mm4 μ),
Column temperature: 30 DEG C,
Determined wavelength: 235nm,
Flow velocity: 1ml/min,
Sample size: 10 μ l,
Moving phase: pH2.4 phosphate buffered saline buffer (get 1.0g bis-hypophosphite monohydrate potassium dihydrogen, add water and make dissolving and be diluted to 1000ml, with phosphoric acid regulate pH=2.4) for mobile phase A, with acetonitrile-ethanol (60:40) for Mobile phase B; Linear gradient elution is carried out by table 1.
The test condition of table 1 HPLC
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 80 | 20 |
| 5 | 80 | 20 |
| 30 | 30 | 70 |
| 35 | 80 | 20 |
| 45 | 80 | 20 |
The stability of embodiment 8 product
The stability experiment of Type B and C N-type waferN is tested with reference to the method described in Chinese Pharmacopoeia 2010 editions two annex XIX C herein.
Table 2 stability test result
Test of long duration at high temperature, high light and 25 DEG C, C N-type waferN is thermodynamically stable, is therefore specially adapted to pharmaceutical preparation.
Embodiment 9 water absorbability
Measure with reference to the method described in Chinese Pharmacopoeia 2010 editions two annex XIX J, be the water absorbability of testing example preparing product under the condition of 75% in relative humidity, result is as shown in table 3 below.
Water absorbability when table 3 relative humidity is 75%
| Sample | 0 day water-content (%) | 3 days | 7 days | 14 days |
| C N-type waferN | 0.386 | 0.422 | 0.436 | 0.489 |
Claims (10)
1. the crystal of Sorafenib Tosylate, is characterized in that, use Cu-K α radiation, it is in X-ray powder diffraction, is that 7.34 °, 18.03 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 ° places have diffraction peak at 2 θ.
2. the crystal of claim 1, has diffraction peak at 7.34 °, 8.2 °, 9.25 °, 10.4 °, 11.27 °, 12.25 °, 13.72 °, 14.69 °, 15.29 °, 16.26 °, 17.31 °, 18.03 °, 19.55 °, 20.15 °, 20.77 °, 22.04 °, 22.43 °, 23.21 °, 24.41 °, 24.64 °, 29.6 ° places.
3. the crystal of claim 1, its have substantially as shown in Figure 1 XRD figure spectrum.
4. the crystal of Sorafenib Tosylate, is characterized in that, uses Cu-K α radiation, in X-ray powder diffraction, is about 7.61 ° and there is diffraction peak at 16 ° of-27 ° of places at 2 θ.
5. the Sorafenib Tosylate crystal of claim 4, its have substantially as shown in Figure 2 XRD figure spectrum.
6. the preparation method of any one of claim 1-3 crystal, comprises the tetrahydrofuran solution preparing Xarelto, and gained solution is lowered the temperature, and adds tosic acid or its hydrate, crystallization, is separated and obtains crystal.
7. the preparation method of claim 6, temperature when wherein solution is cooled to crystallization remains on 10 DEG C ~-80 DEG C.
8. the preparation method of crystal described in claim 4 or 5, comprises the crystal drying under reduced pressure at 40 DEG C ~ 80 DEG C described in any one of claim 1-3.
9. a preparation method for amorphous Sorafenib Tosylate, the crystal drying under reduced pressure at 80 DEG C ~ 120 DEG C comprised according to any one of claim 1-5 obtains.
10. comprise the pharmaceutical composition of crystal according to any one of claim 1-5 and pharmaceutically acceptable carrier.
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| CN105585523A (en) * | 2015-12-29 | 2016-05-18 | 上海北卡医药技术有限公司 | Novel sorafenib TsOH crystal form as well as preparation method and application thereof |
| CN105651877A (en) * | 2015-12-30 | 2016-06-08 | 神威药业集团有限公司 | Detection method of sorafenib and related substances thereof |
| CN106226421A (en) * | 2016-07-14 | 2016-12-14 | 合肥华方医药科技有限公司 | A kind of Sorafenib Tosylate has the detection method of related substance |
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| WO2017101548A1 (en) * | 2015-12-14 | 2017-06-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof |
| CN109796400A (en) * | 2017-11-16 | 2019-05-24 | 四川科伦药物研究院有限公司 | A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof |
| RU2766288C2 (en) * | 2020-03-30 | 2022-03-11 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Amorphous form of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-n-methylpyridine-2-carboxamide tosylate (versions), method for production and use thereof for treatment of oncological diseases |
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| WO2017101548A1 (en) * | 2015-12-14 | 2017-06-22 | Chia Tai Tianqing Pharmaceutical Group Co., Ltd. | Sorafenib hemi-p-tosylate monohydrate crystal and preparation process thereof |
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| CN109796400A (en) * | 2017-11-16 | 2019-05-24 | 四川科伦药物研究院有限公司 | A kind of toluenesulfonic acid Sorafenib crystal form and preparation method thereof |
| CN109796400B (en) * | 2017-11-16 | 2022-07-29 | 四川科伦药物研究院有限公司 | Sorafenib tosylate crystal form and preparation method thereof |
| RU2766288C2 (en) * | 2020-03-30 | 2022-03-11 | Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" | Amorphous form of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)-amino]phenoxy}-n-methylpyridine-2-carboxamide tosylate (versions), method for production and use thereof for treatment of oncological diseases |
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