CN105439947A - Novel crystal form of sorafenib tosylate and preparation method for novel crystal form - Google Patents
Novel crystal form of sorafenib tosylate and preparation method for novel crystal form Download PDFInfo
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Abstract
The invention relates to a novel crystal form of sorafenib tosylate and a preparation method for the novel crystal form. The XRPD spectrum of the crystal form comprises diffraction peaks represented by the following 2theta angles: 4.3 degrees, 13.1 degrees, 16.5 degrees, 17.7 degrees, 19.9 degrees, 20.3 degrees, 20.7 degrees, 21.3 degrees and 22.7 degrees, wherein the error is +/-0.2 degree. The crystal form can be obtained by the steps of adding a sorafenib tosylate raw material into a polar organic solvent, controlling the temperature at 20-100 DEG C and dissolving the raw materials, and then adding an inert solvent for crystallization. The crystal of the obtained crystal form is white to slightly yellowish-brown crystal powder, wherein the purity can reach over 99.8%, the total impurities do not exceed 0.2%, and a potential genotoxic impurity SL-5 can be controlled to not exceed 200ppm. The crystal form is easy to prepare and has good stability.
Description
Technical field
The present invention relates to new crystal of a kind of cancer therapy drug and preparation method thereof, be specifically related to a kind of Sorafenib Tosylate new crystal K crystal formation and preparation method thereof.
Background technology
Sorafenib Tosylate is a kind of novel Mutiple Targets antitumor drug, developed by Bayer A.G, trade(brand)name " Nexavar ", in December, 2005 FDA approval listing, this product was mainly used in treating inoperable advanced renal cell carcinoma and cannot performs the operation or former hepatocellular carcinoma of distant metastasis in Discussion on Chinese Listed in November, 2006.
Sorafenib Tosylate is oral Mutiple Targets, multi-kinase inhibitor, and it has dual anti-tumour effect, on the one hand by suppressing the kinase whose activity of RAF-1 and BRAF, blocks RAS/RAF/MEK/ERK signal transduction pathway, direct inhibition tumor cell propagation; On the other hand, by suppressing the activity of several tyrosine kinase receptor (comprising VEGFR-2, VEGFR-3, PDGFR-b, C-KIT and FLT3), block tumor angiogenesis, the growth of indirect inhibition tumor cell, thus play antineoplastic action.Sorafenib Tosylate as first multi-kinase inhibitor better tolerance, drug effect obviously, convenient oral, at treatment advanced renal cell cancer and liver cancer, there is greater advantage, good as broad-spectrum anti-cancer drug potential applicability in clinical practice.
Bayer AG discloses Sorafenib Tosylate compound patent (CN00802685.8), then 5 kinds of crystal formations (CN200580040775.0) such as Sorafenib Tosylate polymorphic form I, polymorphic form II, polymorphic form III, Methanol Solvate and alcohol solvent compound are again disclosed, define the value (55) of X-ray diffraction 2 θ of polymorphic form I, also disclose the method being prepared polymorphic form I, polymorphic form III, Methanol Solvate and alcohol solvent compound by polymorphic form II simultaneously.
Huahai Pharmaceutical Co., Ltd., Zhejiang discloses polymorphic A (CN201210190995.3) and sorafenib free-alkali polycrystal form I (201210249228.5) subsequently, Qilu Pharmaceutical Co., Ltd. discloses Xarelto crystal form A (CN201210349476.7), Shanghai Chuangnuo Pharmaceutical Co., Ltd. discloses the polymorphic form (NMP-1 of Xarelto tosilate N-Methyl pyrrolidone solvate, NMP-2, NMP-3), in above-mentioned patent, there is in all unexposed described crystal formation the residual of latent gene toxic impurities SL-5, and the residual limit of SL-5.
In order to improve the quality of products, stricter control latent gene toxic impurities SL-5's is residual, in the urgent need to seeking a kind of crystal formation of satisfying the demand.
Summary of the invention
An object of the present invention is to provide a kind of new Sorafenib Tosylate crystal formation, called after K crystal formation, and this crystal formation is easy to preparation, has satisfactory stability and preparations shaping.The composition prepared by the Sorafenib Tosylate of K crystal formation, embodies good In Vitro Dissolution character, and good bioavailability.
More of paramount importancely be, all containing impurity SL-5 (chemical name: 4-(4-amino-benzene oxygen)-N-picoline-2-methane amide in Sorafenib Tosylate raw material and sheet, structural formula is as follows), impurity SL-5 is not only process contaminants, also be degraded product simultaneously, and this impurity has latent gene toxic fragment, therefore need strictly to control its limit.According to EMEA governing principle " GUIDELINEONTHELIMITSOFGENOTOXICIMPURITIES ", by following calculation formula:
Limit according to EMEA governing principle method of calculation SL-5 should be 0.00188%, but this impurity is not genotoxicity impurity, but the impurity containing latent gene toxicity segment, limit with reference to having latent gene toxic fragment impurity in European Pharmacopoeia exposure draft draft imatinib mesylate raw material standard: the limit of 3-acetylpyridine is 0.02%, maximum day dose of Sorafenib Tosylate is 800mg, consistent with imatinib mesylate, therefore with reference to the limit of 3-acetylpyridine, formulate SL-5 limit and must not be 200ppm, in K crystal formation Sorafenib Tosylate provided by the invention, impurity SL-5 can be strict controlled in limit specialized range.
The patent CN200580040775.0.X of Bayer A.G of Yuan Yan producer application is I crystal Sorafenib Tosylate, by carrying out stability comparative study in long-term 24 months to 3 batches of K crystal formation Sorafenib Tosylates provided by the invention and self-control 1 batch of I crystal (preparing I crystal according to the method for Chinese patent CN200580040775.0.X) Sorafenib Tosylate, result shows that SL-5's in I crystal Sorafenib Tosylate is residual far above K crystal formation Sorafenib Tosylate (detailed data the results are shown in embodiment 6, table 4) of the present invention.K crystal formation Sorafenib Tosylate provided by the invention is placed 24 months indices and is still met the requirements, and illustrates that K crystal formation Sorafenib Tosylate places that quality is more stable, security is higher for a long time.
Sorafenib Tosylate K crystal formation provided by the invention, has new crystal formation feature through X-ray diffraction method (XRPD) confirmation.
The XRPD collection of illustrative plates of Sorafenib Tosylate K crystal formation provided by the invention comprises the diffraction peak shown in following 2 θ angles: 4.3 °, 13.1 °, 16.5 °, 17.7 °, 19.9 °, 20.3 °, 20.7 °, 21.3 °, 22.7 °, error is ± 0.2 °.
Further, the XRPD collection of illustrative plates of Sorafenib Tosylate K crystal formation provided by the invention comprises the diffraction peak shown in following 2 θ angles: 14.6 °, 18.7 °, 19.2 °, 24.36 °, 26.4 °, 28.0 °, 28.5 °, 30.9 °, 33.7 °, error is ± 0.2 °.
Again further, the XRPD collection of illustrative plates of Sorafenib Tosylate K crystal formation provided by the invention comprises the diffraction peak shown in following 2 θ angles: 10.9 °, 15.9 °, 23.2 °, 23.5 °, 23.9 °, 24.9 °, 25.2 °, 25.8 °, 27.2 °, 29.4 °, 29.7 ° 39.1 ° 41.0 ° 45.9 °, error is ± 0.2 °.
Further, the XRPD data of Sorafenib Tosylate K crystal formation provided by the invention are as shown in table 1.
Table 1 methylsulfonic acid Xarelto K crystal form X RPD diffractogram 2 θ angle and relative intensity
| 2 θ angles | Relative intensity (Area%) |
| 4.3 | 20.9 |
| 10.9 | 2.5 |
| 13.1 | 100 |
| 14.6 | 7.5 |
| 15.9 | 1.5 |
| 16.5 | 19.8 |
| 17.7 | 41.3 |
| 18.6 | 7.3 |
| 19.2 | 8.7 |
| 19.9 | 15.2 |
| 20.3 | 26.9 |
| 20.7 | 10.3 |
| 21.3 | 32.8 |
| 22.7 | 29.1 |
| 23.2 | 4.1 |
| 23.5 | 1.2 |
| 23.9 | 3.9 |
| 24.36 | 5.9 |
| 24.9 | 3.2 |
| 25.2 | 2.2 |
| 25.8 | 3.1 |
| 26.4 | 7.1 |
| 27.2 | 1.7 |
| 28.0 | 6.0 |
| 28.5 | 9.4 |
| 29.4 | 3.9 |
| 29.7 | 3.0 |
| 30.9 | 6.3 |
| 33.7 | 6.2 |
| 39.1 | 2.4 |
| 41.0 | 3.1 |
| 45.9 | 4.5 |
Further, Sorafenib Tosylate K crystal formation provided by the invention, has XRPD collection of illustrative plates as shown in Figure 1.
Due to the difference of measuring condition, on XRPD diffractogram, the 2 θ angles at each peak and relative intensity can change to some extent, and general 2 θ angles changes are within ± 0.2 °, and relative intensity thinks reasonable error within ± 0.2%.
The present invention also provides the preparation method of described Sorafenib Tosylate K crystal formation, and the method directly can obtain Sorafenib Tosylate K crystal formation of the present invention, and reaction conditions is gentle, and aftertreatment is simple.
The preparation method of Sorafenib Tosylate K crystal formation provided by the invention comprises the steps:
The Sorafenib Tosylate raw material of other crystal formations as I crystal or II crystal formation is added in polar organic solvent, temperature control 20-100 DEG C of reaction, preferred 20-70 DEG C, the preferred DMF of polar organic solvent or N,N-dimethylacetamide, then inert solvent stirring and crystallizing is added, the preferred acetone of inert solvent, ethyl acetate, filtration drying, K crystal formation Sorafenib Tosylate.
Also can be that the Sorafenib Tosylate of other crystal formations as I crystal or II crystal formation is dissolved in polar organic solvent, temperature control 20-100 DEG C of reaction, preferred 20-70 DEG C, the preferred DMF of polar organic solvent or N,N-dimethylacetamide, then inert solvent crystallization is added, the preferred acetone of inert solvent, ethyl acetate, add a small amount of K crystal formation as crystal seed, can obtain K crystal formation Sorafenib Tosylate.
Generally, the consumption of polar organic solvent does not need accurate control, is as the criterion to dissolve solute, different solubility under differing temps; Inert solvent consumption does not need accurate control yet, is as the criterion to reach crystallization object; Owing to being adopt inert solvent crystallization, so amount of seed does not need accurate control yet, adding crystal seed can accelerate crystallization, and improves crystallize out state, and as grain size, color and luster etc., these all belong to the basic theoretical knowledge of those skilled in the art.
The Sorafenib Tosylate of other crystal formations as I crystal or II crystal formation is prepared with reference to existing document patent for Buddhist nun, and purity more than 99.0%.
Sorafenib Tosylate K crystal formation preparation technology provided by the invention, product purity can reach more than 99.8%, yield more than 80%.
Sorafenib Tosylate K crystal formation provided by the invention, crystal is white extremely slightly filemot crystalline powder, and measuring its fusing point by Chinese Pharmacopoeia 2010 editions is 223-231 DEG C.Crystal purity reaches more than 99.8%, total assorted is no more than 0.2%, and latent gene toxic impurities SL-5 can control be no more than 200ppm, not even more than 100ppm, is minimumly no more than 50ppm.
Inert solvent of the present invention refers to the solvent of not having an effect with solute.
Measure its solvability, method with reference to Chinese Pharmacopoeia version in 2010 two notes on the use: it is appropriate to get this product, adds each solvent respectively, in powerful jolting 30 second every 5 minutes, observe the dissolving situation in 30 minutes, to obtain final product, to the results are shown in Table 2.
Table 2 dissolubility test result
The invention has the beneficial effects as follows: crystal formation is easy to preparation, has satisfactory stability; Foreign matter content is low, and particularly latent gene toxic impurities SL-5 content is very low; Long-term placement quality is more stable, security is higher.
Accompanying drawing explanation
The XRPD figure of the Sorafenib Tosylate K crystal formation product of accompanying drawing 1 embodiment 1 preparation.
Embodiment
Following examples illustrate of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1: the preparation of Sorafenib Tosylate K crystal formation
Add the Sorafenib Tosylate 10.0g of I crystal in reaction flask, N,N-dimethylacetamide 50ml, 20 DEG C are stirred 15min, add acetone 300ml crystallization, stir 15h, filtration drying, obtains white solid 7.97g, purity 99.85%, yield 79.7%, fusing point 223-231 DEG C.
Embodiment 2: the preparation of Sorafenib Tosylate K crystal formation
Add the Sorafenib Tosylate 8.0g of I crystal in reaction flask, DMF 45ml, 40 DEG C are stirred 10min, add ethyl acetate 225ml crystallization, stir 12h, filtration drying, obtains white solid 6.50g, purity 99.88%, yield 81.3%, fusing point 223-231 DEG C.
Embodiment 3: the preparation of Sorafenib Tosylate K crystal formation
The Sorafenib Tosylate 12.0g of I crystal is added in reaction flask, DMF 90ml, 100 DEG C are stirred 10min, add acetone 500ml, add a small amount of K Form seeds crystallization, stir 15h, filtration drying, obtain white solid 10.28g, purity 99.81%, yield 85.7%, fusing point 223-231 DEG C.
Embodiment 4: the preparation of Sorafenib Tosylate K crystal formation
The Sorafenib Tosylate 9.0g of II crystal formation is added, DMF and N in reaction flask, the each 40ml of N-N,N-DIMETHYLACETAMIDE, 70 DEG C are stirred 10min, add ethyl acetate 600ml, add a small amount of K crystal seed crystallization, stir 18h, filtration drying, obtains white solid 7.51g, purity 99.83%, yield 83.4%, fusing point 223-231 DEG C.
Embodiment 5: the preparation of Sorafenib Tosylate K crystal formation
The Sorafenib Tosylate 10.0g of II crystal formation is added in reaction flask, DMF 60ml, 50 DEG C are stirred 10min, add each 350ml of acetoneand ethyl acetate, add a small amount of K crystal seed crystallization, stir 15h, filtration drying, obtain white solid 8.27g, purity 99.90%, yield 82.7%, fusing point 223-231 DEG C.
Embodiment 6: Sorafenib Tosylate K crystal formation and I crystal simultaneous test
We adopt homemade embodiment 1-3K crystal formation Sorafenib Tosylate and self-control 1 batch of I crystal (preparing I crystal according to the method for Chinese patent CN200580040775.0.X) Sorafenib Tosylate to carry out comparative study, and detailed results sees the following form.Brand-new sample comparing result, the results are shown in Table 3
Table 30 day comparative test result
Result shows, K crystal formation and I crystal Sorafenib Tosylate are 0 day time, and in I crystal, latent gene toxic impurities SL-5 is apparently higher than K crystal formation.
Test of long duration comparing result
Above-mentioned 4 batches of raw materials are placed in 25 DEG C ± 2 DEG C, place 24 months under 60 ± 10% conditions, detect by stability high spot reviews project, the results are shown in Table 4.
Table 4 test of long duration comparing result
Result shows: K crystal formation and I crystal raw material, its permanent stability experiment in sundry item no significant difference, but in I crystal latent gene toxic impurities SL-5 apparently higher than K crystal formation.
Claims (12)
1. the K crystal formation of a Sorafenib Tosylate, it is characterized in that, X-ray powder diffraction (XPRD) collection of illustrative plates of described K crystal formation comprises the diffraction peak shown in following 2 θ angles: 4.3 °, 13.1 °, 16.5 °, 17.7 °, 19.9 °, 20.3 °, 20.7 °, 21.3 °, 22.7 °, error is ± 0.2 °.
2. the K crystal formation of Sorafenib Tosylate as claimed in claim 1, it is characterized in that, X-ray powder diffraction (XPRD) figure of described K crystal formation also has characteristic peak at following 2 θ angles: 14.6 °, 18.7 °, 19.2 °, 24.36 °, 26.4 °, 28.0 °, 28.5 °, 30.9 °, 33.7 °, error is ± 0.2 °; Preferably also has following characteristics peak: 10.9 °, 15.9 °, 23.2 °, 23.5 °, 23.9 °, 24.9 °, 25.2 °, 25.8 °, 27.2 °, 29.4 °, 29.7 ° 39.1 ° 41.0 ° 45.9 °, error is ± 0.2 °.
3. the K crystal formation of Sorafenib Tosylate as claimed in claim 1 or 2, it is characterized in that, described K crystal form X-ray powder diffraction (XPRD) spectrum data is:
4. the K crystal formation of Sorafenib Tosylate as claimed in claim 3, it is characterized in that, described K crystal form X-ray powder diffraction (XPRD) spectrum data is:
5. the K crystal formation of Sorafenib Tosylate as described in as arbitrary in claim 1-4, it is characterized in that, described K crystal formation has X-ray powder diffraction (XPRD) figure as shown in Figure 1.
6. as described in as arbitrary in claim 1-4, the K crystal formation of Sorafenib Tosylate, is characterized in that, the crystal of described K crystal formation is that white is to slightly filemot crystalline powder.
7. the K crystal formation of Sorafenib Tosylate as described in as arbitrary in claim 1-4, it is characterized in that, the crystalline melting point of described K crystal formation is 223-231 DEG C.
8. as described in as arbitrary in claim 5-7, the preparation method of Sorafenib Tosylate K crystal formation, is characterized in that, comprise the steps:
Add in polar organic solvent by Sorafenib Tosylate raw material, temperature control 20-100 DEG C of dissolving, preferred temperature control 20-70 DEG C, then adds inert solvent crystallization, Sorafenib Tosylate K crystal formation; Described polar organic solvent is DMF and N,N-dimethylacetamide at least one; Described inert solvent is at least one in acetoneand ethyl acetate.
9. the preparation method of Sorafenib Tosylate K crystal formation as claimed in claim 8, it is characterized in that, described Sorafenib Tosylate raw material is I crystal or the II crystal formation of Sorafenib Tosylate, purity more than 99.8%.
10. the preparation method of Sorafenib Tosylate K crystal formation as claimed in claim 8, is characterized in that, add Sorafenib Tosylate K crystal formation as crystal seed when also comprising crystallization.
11. as arbitrary in claim 8-10 as described in the preparation method of Sorafenib Tosylate K crystal formation, it is characterized in that, the yield more than 80% of described Sorafenib Tosylate K crystal formation.
12. as arbitrary in claim 8-11 as described in the preparation method of Sorafenib Tosylate K crystal formation, it is characterized in that, the purity more than 99.8% of described Sorafenib Tosylate K crystal formation; Total mixing is no more than 0.2%, and maximum list is assorted is no more than 0.02%; Latent gene toxic impurities SL-5 is no more than 200ppm, preferably more than 100ppm, more preferably no more than 50ppm.
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| CN106748996A (en) * | 2017-01-14 | 2017-05-31 | 山东裕欣药业有限公司 | A kind of Sorafenib Tosylate crystal-form compound and preparation method thereof |
| CN107011262A (en) * | 2017-06-01 | 2017-08-04 | 中国药科大学 | A kind of method that Sorafenib Tosylate polymorphic K particulates are prepared based on supercritical anti-solvent technology |
| CN107759517A (en) * | 2016-08-23 | 2018-03-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of preparation method of Sorafenib Tosylate crystal formation I |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107759517A (en) * | 2016-08-23 | 2018-03-06 | 广州白云山医药集团股份有限公司白云山制药总厂 | A kind of preparation method of Sorafenib Tosylate crystal formation I |
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| CN106748996B (en) * | 2017-01-14 | 2020-03-20 | 山东裕欣药业有限公司 | Sorafenib tosylate crystal compound and preparation method thereof |
| CN107011262A (en) * | 2017-06-01 | 2017-08-04 | 中国药科大学 | A kind of method that Sorafenib Tosylate polymorphic K particulates are prepared based on supercritical anti-solvent technology |
| CN107011262B (en) * | 2017-06-01 | 2019-10-29 | 中国药科大学 | A method of Sorafenib Tosylate polymorphic K particle is prepared based on supercritical anti-solvent technology |
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| CN110204483B (en) | 2021-06-29 |
| CN110204483A (en) | 2019-09-06 |
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Application publication date: 20160330 |