CN104974133A - Imatinib methanesulfonate crystal form and preparation method thereof - Google Patents
Imatinib methanesulfonate crystal form and preparation method thereof Download PDFInfo
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- CN104974133A CN104974133A CN201410139481.4A CN201410139481A CN104974133A CN 104974133 A CN104974133 A CN 104974133A CN 201410139481 A CN201410139481 A CN 201410139481A CN 104974133 A CN104974133 A CN 104974133A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
The invention relates to a new crystal form M of imatinib methanesulfonate. The crystal form has a characteristic peak on an XRPD (X-ray powder diffraction) spectrum when the 2theta angle is 20.0 degrees, and the intensity of the characteristic peak is 80-90% of that of the strongest peak. The XRPD spectrum has 11 peaks with the relative intensity of higher than 20%, of which the peak positions are respectively 9.8 degrees, 14.1 degrees, 14.8 degrees, 17.6 degrees, 18.3 degrees, 20.1 degrees, 20.7 degrees, 21.2 degrees, 22.2 degrees, 22.8 degrees and 23.8 degrees.
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 imatinib mesylate new crystal form M crystal formation and preparation method thereof.
Background technology
Imatinib mesylate is a kind of selectivity tyrosine kinase inhibitor of Novartis Co., Ltd of Switzerland exploitation, belongs to aniline quinazoline compounds.FDA ratifies imatinib mesylate May calendar year 2001 and is used for the treatment of chronic lymphocytic leukemia, and in February, 2002, FDA ratified the treatment of this medicine for gastrointestinal stromal tumors further.
Imatinib mesylate all can suppress Bcr-Abl Tyrosylprotein kinase in vivo and in vitro on a cellular level, can Selective depression Bcr-Abl positive cell line cell, the chronic myelocytic leukemia of Ph chromatin-positive and the fresh cells of acute lymphoblastic leukemia patient propagation and induce its apoptosis.In addition, imatinib mesylate also can suppress platelet derived growth factor (PDGF) acceptor, STEM CELL FACTOR (SCF), the Tyrosylprotein kinase of c-Kit acceptor, thus suppresses by the cell behavior of PDGF and SCF mediation.
Imatinib mesylate is first appropriate design exploitation after the cause of disease of clear and definite cancer, and achieve the anti-tumor medicine of remarkable effect, the developing milestone of tyrosine kinase inhibitor is not only in succeeding in developing of it, more can be described as a milestone of cancer therapy.
Imatinib mesylate compound is open by Xi Ba-Geiz stock Corp (Novartis Co., Ltd) the earliest, and Chinese patent is CN93103566.X.Novartis Co., Ltd successively discloses α, β, F, G, H, I, K, δ, ε and the armorphous form (CN98807303.X, CN200680044007.7, CN200880018651.6 and CN201010586080.5) of this compound, and set forth beta crystal for most stable crystal form, other crystal formations at normal temperatures, especially easily change beta crystal into when having water, alcohol, ketone to exist.
Subsequently, NATCO PHARMA LTD successively discloses α 2 type crystal formation and I and II type crystal formation (US2008255138, WO2006054314); HETERO DRUGS LTD discloses H1 type crystal formation (US2005234069); Nanjing Cavan Dixu Biologicgal Enginnering Technology Co., Ltd, Yan Rong apply for imatinib mesylate polymorph I and II(CN201110032923.1, CN201110141335.1); Jiangsu Haosen Pharmaceutical Co., Ltd, Jiangsu Hansoh Medical Research Institute Co., Ltd. disclose crystal form A (CN201010176726.2); Polymorphic form N, polymorphic form Y, polymorphic form Z are open by WO2011108953, WO2011100282, WO2011100282 respectively.
It is worth noting, Europe drug assessment office EMEA is in April, 2013, propose governing principle " GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES " and the European Pharmacopoeia exposure draft draft for imatinib, wherein for the impurity T4 with genotoxicity, formulate limit and must not be 2ppm/ days.In above-mentioned patent, in all unexposed described crystal formation, the content of impurity T4 how, and the content of how control T4.
For imatinib mesylate commercialized product, specify that its validity period is 24 months, but the present inventor finds, beta crystal long-term 24 months results of stability show, in preparation, the content of T4 is 3.69ppm, has exceeded regulation, refers to the embodiment of the present invention 7.
In order to better meet EMEA in the governing principle of imatinib for the restriction of T4 content, urgent wish to seek 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 Crystal form of imatinib mesylate, the present invention is by its called after M crystal formation, this crystal formation is easy to preparation, has satisfactory stability and preparations shaping, for imatinib mesylate provides new selection in the application of medicine industry.The composition prepared by the imatinib mesylate of this M crystal formation, embodies good In Vitro Dissolution character, and good bioavailability.
More of paramount importancely be, all containing impurity T4(chemical name: N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine in imatinib mesylate raw material and sheet), structural formula is as follows, impurity T4 is not only process contaminants, also be degraded product simultaneously, and this impurity has potential genotoxicity, therefore need strictly to control its limit.FDA in 2003 ratifies GLEEVEC(and imatinib mesylate) when being used for the treatment of the adult patient and other two kinds of diseases that can not excise and/or occur the malignant gastrointestinal mesenchymal neoplasm shifted, requirement is not given to the existence of T4 and content.
Until 2013, Europe drug assessment office EMEA proposes the governing principle " GUIDELINE ON THE LIMITS OF GENOTOXIC IMPURITIES " for imatinib, the limit of T4 is calculated as follows: maximum day dose of imatinib mesylate is 800mg according to this governing principle, i.e. 0.8g/ days, TTC is that toxicology pays close attention to threshold value, and the genotoxicity impurity namely taking in 1.5 μ g every day to accept.
Formulate T4 limit with reference to EMEA governing principle and European Pharmacopoeia exposure draft draft and must not be 2ppm, in M crystal formation imatinib mesylate provided by the invention, impurity T4 can be strict controlled in limit specialized range.
The raw material DMF applied at FDA according to Yuan Yan producer and apply for a patent CN98807303.X and infer that commercial preparation imatinib mesylate (methylsulfonic acid imatinib tablet agent) is prepared from by beta crystal bulk drug, stability comparative study in long-term 30 months is carried out by 3 batches of tablets preparing M crystal formation provided by the invention and commercial preparation, result shows that the content of T4 in commercial preparation is 3.69ppm, has exceeded and has limited regulation; And T4 content all the results are shown in embodiment 7, table 4 more than 2ppm(detailed data in 3 batches of tablet samples provided by the invention).The validity period of current commercialized product imatinib mesylate is 24 months, and M crystal formation provided by the invention is placed 30 months indices after making tablet and still met the requirements, and illustrates that M crystal formation imatinib mesylate places that quality is more stable, security is higher for a long time.
The invention provides a kind of imatinib mesylate M crystal formation, use Cu-K α radiation, have characteristic peak with the powder x-ray diffraction that 2 θ angles (°) represent at 20.0 °, its intensity is the 80%-90% of highest peak.
Imatinib mesylate M crystal formation provided by the present invention, use Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°), the peak of relative intensity more than 20% has 11, and peak position is respectively 9.8 °, 14.1 °, 14.8 °, 17.6 °, 18.3 °, 20.1 °, 20.7 °, 21.2 °, 22.2 °, 22.8 ° and 23.8 °.
Further, imatinib mesylate M crystal formation provided by the present invention, uses Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°) peak position 2 θ at 11 peaks of relative intensity more than 20% and relative intensity as shown in table 1.
Table 1
Further, imatinib mesylate M crystal formation provided by the present invention, use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°) as shown in Figure 1.
Due to the difference of measuring condition, on x-ray diffraction pattern, 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%.
Imatinib mesylate M crystal formation provided by the invention, measuring its fusing point by Chinese Pharmacopoeia 2010 editions is 217-222 DEG C, purity more than 99.7%.
The present invention also provides the preparation method of described imatinib mesylate M crystal formation, and the method directly can obtain imatinib mesylate M crystal formation of the present invention, and technique is simple, mild condition.
The preparation method of imatinib mesylate M crystal formation provided by the invention comprises the steps: other crystal formations as alpha-crystal form or unformed imatinib mesylate are dissolved in polar organic solvent, temperature control 20-60 DEG C, preferred 40-50 DEG C, polar organic solvent particular methanol, optionally add appropriate M crystal formation as crystal seed, crystallization, obtains M type imatinib mesylate.
Other crystal formations such as alpha-crystal form or unformed imatinib mesylate are prepared with reference to existing document patent.
The purity of imatinib mesylate M crystal formation preparation technology provided by the invention can reach more than 99.7%
The M crystal formation imatinib mesylate of gained of the present invention is that white is to light yellow crystalline powder.
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.The results are shown in Table 2.The M crystalline form imatinib mesylate of visible gained of the present invention meets the deliquescent regulation of bulk drug.
Table 2 dissolubility test result
Accompanying drawing explanation
The XRPD figure of the imatinib mesylate M 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 imatinib mesylate M crystal formation
Add the imatinib mesylate 8.0g of alpha-crystal form in reaction flask, methyl alcohol 100ml, reaction system is heated to 40 DEG C; Stir 10min, remove partial solvent under reduced pressure, stir 10h, filtration drying, obtains white solid 5.32g, purity 99.81%, yield 66.5%, fusing point 219-220 DEG C.
Embodiment 2: the preparation of imatinib mesylate M crystal formation
Add the imatinib mesylate 15.0g of alpha-crystal form in reaction flask, methyl alcohol 180ml, reaction system is heated to 45 DEG C; Stir 15min, remove partial solvent under reduced pressure, stir 12h, filtration drying, obtains white solid 10.4g, purity 99.87%, yield 69.3%, fusing point 218-220 DEG C.
Embodiment 3: the preparation of imatinib mesylate M crystal formation
Add unformed imatinib mesylate 12.0g in reaction flask, methyl alcohol 160ml, reaction system is heated to 50 DEG C; Stir 10min, remove partial solvent under reduced pressure, stir 15h, filtration drying, obtains white solid 8.17g, purity 99.85%, yield 68.1%, fusing point 220-222 DEG C.
Embodiment 4: the preparation of imatinib mesylate M crystal formation
Add the imatinib mesylate 21.0g of alpha-crystal form in reaction flask, methyl alcohol 320ml, reaction system is heated to 50 DEG C; Stir 15min, add M crystal seed 0.2g, stir 12h, filtration drying, obtains white solid 18.6g, purity 99.79%, yield 88.5%, fusing point 219-220 DEG C.
Embodiment 5: the preparation of imatinib mesylate M crystal formation
Add the imatinib mesylate 25.0g of alpha-crystal form in reaction flask, methyl alcohol 250ml, reaction system is heated to 40 DEG C; Stir 15min, add M crystal seed 0.3g, stir 15h, filtration drying, obtains white solid 22.3g, purity 99.80%, yield 89.2%, fusing point 217-219 DEG C.
Embodiment 6: the preparation of imatinib mesylate M crystal formation
Add unformed imatinib mesylate 20.0g in reaction flask, methyl alcohol 280ml, reaction system is heated to 40 DEG C; Stir 10min, add M crystal seed 0.1g, stir 15h, filtration drying, obtains white solid 17.6g, purity 99.82%, yield 88.0%, fusing point 218-220 DEG C.
Embodiment 7: with the simultaneous test of beta crystal imatinib mesylate
We adopt homemade 3 batches of M crystal formation imatinib mesylate and self-control 1 batch of beta crystal (preparing beta crystal according to the method for Chinese patent 98807303.X) imatinib mesylate to carry out the comparative study of stability test, and detailed comparisons the results are shown in Table 3.
Table 30 day comparative test result
Result shows, M crystal formation and beta crystal imatinib mesylate are 0 day time, and its indices all meets the requirements.
Test of long duration comparing result
Above-mentioned 4 batch samples are placed in 25 ± 2 DEG C, place under relative humidity 60 ± 10% condition 24 months (validity period of commercialized product imatinib mesylate is 24 months, and the time of therefore herein investigating is decided to be 24 months), detect by stability high spot reviews project, the results are shown in Table 4.
Table 4 test of long duration comparing result
Result shows: M crystal formation and beta crystal imatinib mesylate, sundry item no significant difference in the experiment of its permanent stability, but beta crystal imatinib mesylate, genotoxicity impurity T4 in the validity period of 24 months apparently higher than M crystal formation imatinib mesylate, do not meet the regulation being less than 2ppm.M crystal formation imatinib mesylate, genotoxicity impurity T4 was still less than 2ppm 24 months time.
Claims (10)
1. an imatinib mesylate M crystal formation, it is characterized in that using Cu-K α radiation, have characteristic peak with the powder x-ray diffraction that 2 θ angles (°) represent at 20.0 °, its intensity is the 80%-90% of highest peak.
2. imatinib mesylate M crystal formation as claimed in claim 1, it is characterized in that using Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°), the peak of relative intensity more than 20% has 11.
3. imatinib mesylate M crystal formation as claimed in claim 2, it is characterized in that using Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°), the peak position at 11 peaks of relative intensity more than 20% is respectively 9.8 °, 14.1 °, 14.8 °, 17.6 °, 18.3 °, 20.1 °, 20.7 °, 21.2 °, 22.2 °, 22.8 ° and 23.8 °.
4. imatinib mesylate M crystal formation as claimed in claim 2, is characterized in that using Cu-K α radiation, in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°) peak position 2 θ at 11 peaks of relative intensity more than 20% and relative intensity as follows:
。
5. imatinib mesylate M crystal formation as claimed in claim 1, it is characterized in that using Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°) as shown in Figure 1.
6. imatinib mesylate M crystal formation as claimed in claim 1, is characterized in that the fusing point of described imatinib mesylate M crystal formation is 217-222 DEG C.
7. prepare the method for imatinib mesylate M crystal formation as claimed in claim 1, comprise the steps: the imatinib mesylate of other crystal formations to be dissolved in polar organic solvent, at temperature control 20-60 DEG C, optionally add appropriate M crystal formation as crystal seed, crystallization, obtains M type imatinib mesylate.
8. prepare the method for imatinib mesylate M crystal formation as claimed in claim 7, it is characterized in that, the imatinib mesylate of other crystal formations described is alpha-crystal form or unformed.
9. prepare the method for imatinib mesylate M crystal formation as claimed in claim 7, it is characterized in that described control temperature is 40-50 DEG C.
10. prepare the method for imatinib mesylate M crystal formation as claimed in claim 7, it is characterized in that described organic solvent is methyl alcohol.
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Citations (6)
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|---|---|---|---|---|
| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| US20060173182A1 (en) * | 2003-02-18 | 2006-08-03 | Cipla Limited | Process of preparing imatinib and imatinib prepared thereby |
| US20080275055A1 (en) * | 2007-05-02 | 2008-11-06 | Chemagis Ltd. | Imatinib production process |
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
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Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1264375A (en) * | 1997-07-18 | 2000-08-23 | 诺瓦提斯公司 | Crystal modification of N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use |
| US20060173182A1 (en) * | 2003-02-18 | 2006-08-03 | Cipla Limited | Process of preparing imatinib and imatinib prepared thereby |
| CN101641345A (en) * | 2006-10-26 | 2010-02-03 | 西科尔公司 | Imatinib base, and imatinib mesylate and processes for preparation thereof |
| US20080275055A1 (en) * | 2007-05-02 | 2008-11-06 | Chemagis Ltd. | Imatinib production process |
| WO2008135980A1 (en) * | 2007-05-02 | 2008-11-13 | Chemagis Ltd. | Imatinib production process |
| CN102040587A (en) * | 2009-10-26 | 2011-05-04 | 韩南银 | Preparation method of imatinib mesylate |
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| 张昌军 等: "《有机化学实验》", 31 August 2006, 中国医药科技出版社 * |
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