CN110204483B - Novel crystal form of sorafenib tosylate and preparation method thereof - Google Patents
Novel crystal form of sorafenib tosylate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a novel crystal form of sorafenib tosylate and a preparation method thereof, wherein an XRPD (X-ray diffraction pattern) spectrum of the crystal form comprises diffraction peaks shown by the following 2 theta angles: 4.3 °, 13.1 °, 16.5 °, 17.7 °, 19.9 °, 20.3 °, 20.7 °, 21.3 °, 22.7 °, with an error of ± 0.2 °. The crystal form can be obtained by adding sorafenib tosylate raw material into a polar organic solvent, controlling the temperature to be 20-100 ℃ for dissolution, and then adding an inert solvent for crystallization. The obtained crystal form crystal is white to yellowish brown crystalline powder, the purity can reach more than 99.8 percent, the total impurity is not more than 0.2 percent, and the potential genotoxic impurity SL-5 can be controlled to be not more than 200 ppm. The crystal form is easy to prepare and has good stability.
Description
The invention relates to a divisional application of 201410717357.1, the application date of the original application is 2014, 12 and 01, and the invention is named as a sorafenib tosylate new crystal form and a preparation method thereof.
Technical Field
The invention relates to a new crystal form of an anticancer drug and a preparation method thereof, in particular to a new crystal form K of sorafenib tosylate and a preparation method thereof.
Background
Sorafenib tosylate is a novel multi-target antitumor drug developed and developed by German Bayer company, with the trade name of DuoJimei, approved by FDA in 12 months in 2005 and marketed in China in 11 months in 2006, and is mainly used for treating inoperable late renal cell carcinoma and inoperable or distant metastatic primary hepatocellular carcinoma.
Sorafenib tosylate is an oral multi-target multi-kinase inhibitor, which has dual anti-tumor effects, on one hand, the sorafenib tosylate blocks RAS/RAF/MEK/ERK signal conduction pathways by inhibiting the activities of RAF-1 and BRAF kinase, and directly inhibits the proliferation of tumor cells; on the other hand, the anti-tumor effect is achieved by inhibiting the activity of several tyrosine kinase receptors (including VEGFR-2, VEGFR-3, PDGFR-b, C-KIT and FLT3), blocking the tumor angiogenesis and indirectly inhibiting the growth of tumor cells. The sorafenib tosylate as the first multi-kinase inhibitor has good tolerance, obvious drug effect and convenient oral administration, has great advantages in the aspect of treating late kidney cancer and liver cancer, and has good clinical application prospect as a broad-spectrum anticancer drug.
Bayer discloses a sorafenib tosylate patent (CN00802685.8), then 5 crystal forms (CN200580040775.0) such as sorafenib tosylate polymorph I, polymorph II, polymorph III, methanol solvate and ethanol solvate, and the like, defines the X-ray diffraction 2 theta value (55) of polymorph I, and also discloses a method for preparing polymorph I, polymorph III, methanol solvate and ethanol solvate from polymorph II.
Subsequently, Zhejiang Huahai pharmaceutical industry, Inc. disclosed polymorph A (CN201210190995.3) and sorafenib free base polymorph I (201210249228.5), Qilu pharmaceutical company, Inc. disclosed sorafenib form A (CN201210349476.7), Shanghai Chuno pharmaceutical company, Inc. disclosed sorafenib p-toluenesulfonate N-methylpyrrolidone solvate polymorphs (NMP-1, NMP-2, NMP-3), and none of the above patents disclose the residue of potentially genotoxic impurity SL-5 in the form, and the residue limit of SL-5.
In order to improve the product quality and strictly control the residue of the potential genotoxic impurity SL-5, a crystal form meeting the requirement is urgently required to be searched.
Disclosure of Invention
The invention aims to provide a novel sorafenib tosylate crystal form, named as a K crystal form, which is easy to prepare and has good stability and preparation formability. The composition prepared from the K crystal form of sorafenib tosylate shows good in-vitro dissolution property and good bioavailability.
The most important point is that sorafenib tosylate raw materials and tablets contain impurity SL-5 (chemical name: 4- (4-aminophenoxy) -N-methylpyridine-2-formamide, the structural formula is shown in the specification), the impurity SL-5 is not only a process impurity, but also a degradation product, and the impurity has potential genotoxicity fragments, so the limit of the impurity is strictly controlled. According to EMEA guiding principle GUIDELLINE ON THE LIMITS OF GENOXIC IMPURITIES, the following formula is calculated:
the limit for SL-5 should be 0.00188% calculated according to EMEA guidelines, but this impurity is not a genotoxic impurity but an impurity containing a potentially genotoxic fragment, the limit for impurities having a potentially genotoxic fragment in the raw material standard for imatinib mesylate according to the european pharmacopoeia discussion draft: the limit of the 3-acetylpyridine is 0.02%, the maximum daily dosage of the sorafenib tosylate is 800mg, and the maximum daily dosage is consistent with that of the imatinib mesylate, so that the limit of SL-5 is set to be not more than 200ppm by referring to the limit of the 3-acetylpyridine, and the impurity SL-5 in the sorafenib tosylate in the K crystal form provided by the invention can be strictly controlled within a limit specified range.
Patent CN200580040775.0.X applied by German Bayer company of original research manufacturers is I crystal form sorafenib tosylate, and the long-term 24-month stability comparison research on 3 batches of K crystal form sorafenib tosylate provided by the invention and 1 self-made batch of I crystal form (I crystal form is prepared according to the method of Chinese patent CN200580040775.0.X) sorafenib tosylate shows that the SL-5 residue in I crystal form sorafenib tosylate is far higher than that of K crystal form sorafenib tosylate provided by the invention (the detailed data result is shown in example 6 and table 4). Various indexes of the K crystal form sorafenib tosylate provided by the invention still meet the requirements after being placed for 24 months, which shows that the quality of the K crystal form sorafenib tosylate is more stable and the safety is higher after the K crystal form sorafenib tosylate is placed for a long time.
The sorafenib tosylate K crystal form provided by the invention has new crystal form characteristics after being confirmed by an X-ray diffraction method (XRPD).
The XRPD pattern of the sorafenib tosylate K crystal form provided by the invention comprises diffraction peaks shown by the following 2 theta angles: 4.3 °, 13.1 °, 16.5 °, 17.7 °, 19.9 °, 20.3 °, 20.7 °, 21.3 °, 22.7 °, with an error of ± 0.2 °.
Further, the XRPD pattern of the sorafenib tosylate K crystal form provided by the invention comprises diffraction peaks shown by the following 2 theta angles: 14.6 degrees, 18.7 degrees, 19.2 degrees, 24.36 degrees, 26.4 degrees, 28.0 degrees, 28.5 degrees, 30.9 degrees and 33.7 degrees, and the error is +/-0.2 degrees.
Still further, the XRPD pattern of the sorafenib tosylate crystalline form provided by the invention comprises diffraction peaks shown by the following 2 theta 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 °, with an error of ± 0.2 °.
Further, the XRPD data of the sorafenib tosylate K crystalline form provided by the invention is shown in table 1.
Table 1 sorafenib mesylate form K XRPD diffractogram 2 theta angles and relative intensities
Furthermore, the crystal form of sorafenib tosylate provided by the invention has an XRPD pattern as shown in figure 1.
Due to different measurement conditions, the 2 theta angle and the relative intensity of each peak on the XRPD diffraction pattern can be changed, the 2 theta angle is generally changed within +/-0.2 degrees, and the relative intensity within +/-0.2 percent is considered as a reasonable error.
The invention also provides a preparation method of the sorafenib tosylate K crystal form, the sorafenib tosylate K crystal form can be directly obtained by the method, the reaction condition is mild, and the post-treatment is simple.
The preparation method of the sorafenib tosylate K crystal form provided by the invention comprises the following steps:
adding sorafenib tosylate raw materials of other crystal forms such as crystal form I or crystal form II into a polar organic solvent, controlling the temperature to be 20-100 ℃ for reaction, preferably controlling the temperature to be 20-70 ℃, preferably selecting the polar organic solvent to be N, N-dimethylformamide or N, N-dimethylacetamide, then adding an inert solvent, stirring and crystallizing, preferably selecting acetone and ethyl acetate, filtering and drying to obtain the sorafenib tosylate of the crystal form K.
Or dissolving other crystal forms such as I crystal form or II crystal form sorafenib tosylate in a polar organic solvent, controlling the temperature to be 20-100 ℃ for reaction, preferably controlling the temperature to be 20-70 ℃, preferably selecting N, N-dimethylformamide or N, N-dimethylacetamide as the polar organic solvent, then adding an inert solvent for crystallization, preferably selecting acetone and ethyl acetate as the inert solvent, and adding a small amount of K crystal form as seed crystal to obtain the K crystal form sorafenib tosylate.
In general, the dosage of the polar organic solvent does not need to be accurately controlled, and the solubility is different at different temperatures based on the dissolved solute; the dosage of the inert solvent does not need to be accurately controlled so as to achieve the aim of crystallization; because the inert solvent is adopted for crystallization, the dosage of the seed crystal does not need to be accurately controlled, the addition of the seed crystal can accelerate crystallization and improve the states of the precipitated crystal, such as the size and the color of the crystal grains, and the like, which belong to the basic theoretical knowledge of the technicians in the field.
Other crystal forms such as crystal form I or crystal form II sorafenib tosylate are prepared by reference to the prior literature patents, and the purity is more than 99.0 percent.
According to the preparation process of the sorafenib tosylate K crystal form, the product purity can reach more than 99.8%, and the yield is more than 80%.
The crystal of the sorafenib tosylate K crystal provided by the invention is white to slightly yellowish brown crystalline powder, and the melting point of the crystal is 223-231 ℃ determined according to the 2010 version of Chinese pharmacopoeia. The crystal purity reaches more than 99.8 percent, the total impurities do not exceed 0.2 percent, and the potential genotoxic impurity SL-5 can be controlled to be not more than 200ppm, even not more than 100ppm, and the lowest not more than 50 ppm.
The inert solvent of the present invention means a solvent which does not interact with the solute.
The solubility of the compound is determined by referring to the two general examples of the Chinese pharmacopoeia 2010 edition, and the method comprises the following steps: and (3) taking a proper amount of the product, respectively adding each solvent, strongly shaking for 30 seconds every 5 minutes, and observing the dissolution condition within 30 minutes to obtain the product, wherein the results are shown in Table 2.
Table 2 results of solubility test
The invention has the beneficial effects that: the crystal form is easy to prepare and has good stability; the impurity content is low, particularly the content of a potential genotoxic impurity SL-5 is very low; the quality is more stable and the safety is higher after long-term storage.
Drawings
Figure 1 XRPD pattern of sorafenib tosylate crystalline form product prepared in example 1.
Detailed Description
The following examples are intended to illustrate the present invention and should not be construed as limiting the scope thereof.
Example 1: preparation of sorafenib tosylate K crystal form
Adding 10.0g of sorafenib tosylate of crystal form I and 50ml of N, N-dimethylacetamide into a reaction bottle, stirring for 15min at 20 ℃, adding 300ml of acetone for crystallization, stirring for 15h, filtering and drying to obtain 7.97g of a white solid with the purity of 99.85%, the yield of 79.7% and the melting point of 223-.
Example 2: preparation of sorafenib tosylate K crystal form
Adding 8.0g of sorafenib tosylate of crystal form I and 45ml of N, N-dimethylformamide into a reaction bottle, stirring for 10min at 40 ℃, adding 225ml of ethyl acetate for crystallization, stirring for 12h, filtering and drying to obtain 6.50g of white solid with the purity of 99.88 percent, the yield of 81.3 percent and the melting point of 223-231 ℃.
Example 3: preparation of sorafenib tosylate K crystal form
Adding 12.0g of sorafenib tosylate of crystal form I and 90ml of N, N-dimethylformamide into a reaction bottle, stirring for 10min at 100 ℃, adding 500ml of acetone, adding a small amount of K crystal seed crystals for crystallization, stirring for 15h, filtering and drying to obtain 10.28g of white solid with the purity of 99.81%, the yield of 85.7% and the melting point of 223-.
Example 4: preparation of sorafenib tosylate K crystal form
9.0g of sorafenib tosylate with crystal form II, 40ml of N, N-dimethylformamide and N, N-dimethylacetamide are added into a reaction bottle, stirred for 10min at 70 ℃, 600ml of ethyl acetate is added, a small amount of K seed crystal is added for crystallization, stirred for 18h, filtered and dried to obtain 7.51g of white solid with the purity of 99.83 percent, the yield of 83.4 percent and the melting point of 223-231 ℃.
Example 5: preparation of sorafenib tosylate K crystal form
Adding 10.0g of sorafenib tosylate of crystal form II and 60ml of N, N-dimethylformamide into a reaction bottle, stirring for 10min at 50 ℃, adding 350ml of acetone and ethyl acetate respectively, adding a small amount of K seed crystal for crystallization, stirring for 15h, filtering and drying to obtain 8.27g of white solid with the purity of 99.90 percent, the yield of 82.7 percent and the melting point of 223-231 ℃.
Example 6: comparative test of sorafenib tosylate K crystal form and I crystal form
We used the home-made sorafenib tosylate of the crystal form of example 1-3K and the home-made sorafenib tosylate of batch 1 of crystal form I (prepared according to the method of Chinese patent CN200580040775.0. X), and the detailed results are shown in the following table. Fresh samples were compared and the results are shown in Table 3
TABLE 30 days comparative test results
The result shows that the potential genotoxic impurity SL-5 in the crystal form I is obviously higher than that in the crystal form K when the crystal form K and the crystal form I of sorafenib tosylate are in 0 day.
Long term test comparison results
The 4 batches of raw materials are placed at 25 +/-2 ℃ and 60 +/-10 percent for 24 months, and the detection is carried out according to the key stability investigation items, and the results are shown in table 4.
TABLE 4 Long-term test comparison results
The results show that: the crystal form K and the crystal form I are raw materials, and other items in a long-term stability experiment have no obvious difference, but potential genotoxic impurity SL-5 in the crystal form I is obviously higher than the crystal form K.
Claims (6)
1. A preparation method of sorafenib tosylate K crystal form is characterized by comprising the following steps:
adding sorafenib tosylate raw material into a polar organic solvent, controlling the temperature to be 20-100 ℃ for dissolution, and then adding an inert solvent for crystallization to obtain sorafenib tosylate K crystal form; the polar organic solvent is at least one of N, N-dimethylformamide and N, N-dimethylacetamide; the inert solvent is at least one of acetone and ethyl acetate;
the X-ray powder diffraction (XPRD) pattern of the K crystal form comprises diffraction peaks shown by the following 2 theta angles: 4.3 °, 10.9 °, 13.1 °, 14.6 °, 15.9 °, 16.5 °, 17.7 °, 18.7 °, 19.2 °, 19.9 °, 20.3 °, 20.7 °, 21.3 °, 22.7 °, 23.2 °, 23.5 °, 23.9 °, 24.36 °, 24.9 °, 25.2 °, 25.8 °, 26.4 °, 27.2 °, 28.0 °, 28.5 °, 29.4 °, 29.7 °, 30.9 °, 33.7 °, 39.1 °, 41.0 °, 45.9 °, with an error of ± 0.2 °,
the potential genotoxic impurity SL-5 of the sorafenib tosylate K crystal form is not more than 100 ppm;
the sorafenib tosylate raw material is a sorafenib tosylate crystal I, and the purity is over 99.8 percent;
the structural formula of the SL-5 is as follows:
2. the method for preparing sorafenib tosylate K crystal form according to claim 1, further comprising adding sorafenib tosylate K crystal form as a seed crystal during crystallization.
3. The method for preparing sorafenib tosylate K crystalline form according to any one of claims 1 to 2, wherein the yield of the sorafenib tosylate K crystalline form is above 80%.
4. The method for preparing sorafenib tosylate K crystal form according to any of claims 1 to 2, wherein the purity of the sorafenib tosylate K crystal form is above 99.8%; the total impurity is not more than 0.2 percent, and the maximum single impurity is not more than 0.02 percent.
5. The preparation method of sorafenib tosylate K crystal form of claim 1, wherein dissolution is controlled at a temperature of 20-70 ℃.
6. The method for preparing sorafenib tosylate K crystalline form according to claim 4, wherein the potentially genotoxic impurity SL-5 is not more than 50 ppm.
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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 |
| 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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| EP1797037B1 (en) * | 2004-09-29 | 2014-12-17 | Bayer HealthCare LLC | Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyoxy}n-methylpyridine-2-carboxamide |
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