CN104974133B - A kind of Crystal form of imatinib mesylate and preparation method thereof - Google Patents
A kind of Crystal form of imatinib mesylate and preparation method thereof Download PDFInfo
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- CN104974133B CN104974133B CN201410139481.4A CN201410139481A CN104974133B CN 104974133 B CN104974133 B CN 104974133B CN 201410139481 A CN201410139481 A CN 201410139481A CN 104974133 B CN104974133 B CN 104974133B
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- imatinib mesylate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- 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 present invention relates to a kind of new crystal form M crystal form of imatinib mesylate, there is characteristic peak at the crystal form 2 θ angles on XRPD collection of illustrative plates at 20.0 °, its intensity is 80% the 90% of highest peak.Peak of the relative intensity more than 20% has 11 in XRPD collection of illustrative plates, its 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 °.
Description
Technical field
The present invention relates to a kind of novel crystal forms of cancer therapy drug and preparation method thereof, and in particular to a kind of imatinib mesylate
New crystal form M crystal form and preparation method thereof.
Background technology
Imatinib mesylate is a kind of selective tyrosine kinase inhibitor of Novartis Co., Ltd of Switzerland exploitation, belongs to anilino quinazoline
Oxazoline compound.FDA is used to treat chronic myelogenous leukemia in May, 2001 approval imatinib mesylate, and 2002
2 months FDA of year further ratifies the treatment that the medicine is used for gastrointestinal stromal tumors.
Imatinib mesylate can suppress Bcr-Abl tyrosine kinase on a cellular level in vivo and in vitro, can selectivity
Suppress Bcr-Abl positive cell lines cell, the chronic myelocytic leukemia and acute lymphoblastic leukemia of Ph chromatin-positives
The propagation of the fresh cells of patient and induce its apoptosis.In addition, imatinib mesylate may also suppress platelet derived growth because
Son（PDGF）Acceptor, stem cell factor (SCF), the tyrosine kinase of c-Kit acceptors, so as to suppress by PDGF and SCF mediations
Cell behavior.
Imatinib mesylate is first and exploitation is rationally designed after the cause of disease of clear and definite cancer, and achieves remarkable effect
Anti-tumor medicine, succeeding in developing for it be not only the developing milestone of tyrosine kinase inhibitor, more can be described as cancer
One milestone of disease treatment.
Imatinib mesylate compound is earliest by Xi Ba-Geiz stock Corp（Novartis Co., Ltd）Open, Chinese patent is
CN93103566.X.Novartis Co., Ltd successively discloses α, β, F, G, H, I, K, δ, ε of the compound and armorphous form
（CN98807303.X, CN200680044007.7, CN200880018651.6 and CN201010586080.5）, and elaborate
Beta crystal is most stable crystal form, other crystal forms at normal temperatures, are especially easily changed into beta crystal in the presence of having water, alcohol, ketone.
Then, NATCO PHARMA LTD successively disclose 2 type crystal forms of α and I and II type crystal forms（US2008255138、
WO2006054314）；HETERO DRUGS LTD disclose H1 type crystal forms（US2005234069）；Nanjing all one's life biology work
Journey Technology Co., Ltd., Yan Rong application imatinib mesylate polymorphs I and II（CN201110032923.1、
CN201110141335.1）；Jiangsu Haosen Pharmaceutical Co., Ltd, Jiangsu Hansoh Medical Research Institute Co., Ltd. disclose crystalline substance
Type A（CN201010176726.2）；Polymorph N, polymorph Y, polymorph Z respectively by WO2011108953,
WO2011100282, WO2011100282 are disclosed.
It is worth noting that European drug assessment office EMEA is in April, 2013, it is proposed that guideline《GUIDELINE
ON THE LIMITS OF GENOTOXIC IMPURITIES 》With the European Pharmacopoeia exposure draft draft for Imatinib, its
In for the impurity T4 with genotoxicity, formulate limit and must not be 2ppm/ days.In above-mentioned patent, the undisclosed crystalline substance
How is the content of impurity T4 in type, and how to control the content of T4.
For imatinib mesylate commercialized product, it is specified that its term of validity is 24 months, but the present inventor sends out
Existing, the long-term 24 months results of stability of beta crystal show that the content of T4 is 3.69ppm in preparation, has exceeded regulation, has referred to
The embodiment of the present invention 7.
It is highly desirable to seek in order to better meet EMEA for the restriction in the guideline of Imatinib for T4 contents
Seek a kind of crystal form for meeting needs.
The content of the invention
It is an object of the present invention to providing a kind of new Crystal form of imatinib mesylate, the present invention is named as M
Crystal form, the crystal form is easily prepared, with good stability and preparations shaping, be imatinib mesylate in medical industry
Using providing new selection.The composition prepared by the imatinib mesylate of the M crystal forms, embodies good In Vitro Dissolution
Property, and good bioavilability.
Mostly important is a little to contain impurity T4 in imatinib mesylate raw material and piece（Chemical name：N- (5- ammonia
Base -2- aminomethyl phenyls) -4- (3- pyridine radicals) -2- aminopyrimidines）, structural formula is as follows, and impurity T4 is not only process contaminants, at the same time
And catabolite, and the impurity has potential genotoxicity, therefore its limit need to strictly be controlled.FDA in 2003
Ratify GLEEVEC（That is Gleevec）For treating the adult for the malignant gastrointestinal mesenchymal neoplasm that cannot be cut off and/or shift
Patient and during other two kinds of diseases, the presence to T4 and content do not give requirement.
Until 2013, European drug assessment office EMEA proposed the guideline for Imatinib《GUIDELINE
ON THE LIMITS OF GENOTOXIC IMPURITIES 》, calculate the limit of T4 as follows according to this guideline
Degree：The maximum day dose of imatinib mesylate is 800mg, i.e., 0.8g/ days, and TTC pays close attention to threshold value for toxicology, i.e., takes the photograph daily
The genotoxicity impurity for entering 1.5 μ g is to receive.
T4 limits are formulated with reference to EMEA guidelines and European Pharmacopoeia exposure draft draft and must not be 2ppm, and the present invention carries
Impurity T4 can be strict controlled in limit prescribed limit in the M crystal form imatinib mesylates of confession.
CN98807303.X deduction commercial preparation lattice in the FDA raw material DMF applied and are applied for a patent according to Yuan Yan producers
Row are defended（Beta crystal methylsulfonic acid imatinib tablet）It is to be prepared by beta crystal bulk pharmaceutical chemicals, passes through prepared by M crystal forms provided by the invention
3 batches of tablets and commercial preparation carry out long-term stability comparative study in 30 months, the results showed that the content of T4 is in commercial preparation
3.69ppm, has exceeded restriction regulation；And T4 contents are not less than 2ppm in 3 batches of tablet samples provided by the invention（Detailed data
The result is shown in embodiment 7, table 4）.The term of validity of commercialized product Gleevec is 24 months at present, and M crystal forms provided by the invention are made
30 months indices are placed after tablet to still conform to require, illustrate M crystal forms imatinib mesylate place for a long time quality it is more stable,
Security higher.
The present invention provides a kind of imatinib mesylate M crystal forms, is radiated using Cu-K α, with 2 θ angles（°）The powder of expression
X-ray diffraction has characteristic peak at 20.0 °, its intensity is the 80%-90% of highest peak.
Imatinib mesylate M crystal forms provided by the present invention, are radiated using Cu-K α, with 2 θ angles（°）The powder of expression
Peak of the relative intensity more than 20% has 11 in X-ray diffracting spectrum, 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 forms provided by the present invention, are radiated using Cu-K α, with 2 θ angles（°）
2 θ of peak position at 11 peak of the relative intensity more than 20% and relative intensity are as shown in table 1 in the powder x-ray diffraction collection of illustrative plates of expression.
Table 1
Further, imatinib mesylate M crystal forms provided by the present invention, are radiated using Cu-K α, with 2 θ angles
（°）The powder x-ray diffraction collection of illustrative plates of expression is as shown in Figure 1.
Due to the difference of measuring condition, the 2 θ angles at each peak and relative intensity can change on x-ray diffraction pattern, and general 2
θ angles change within ± 0.2, and relative intensity is considered reasonable error within ± 0.2%.
Imatinib mesylate M crystal forms provided by the invention, it is 217-222 to measure its fusing point by Chinese Pharmacopoeia 2010 editions
DEG C, purity more than 99.7%.
The present invention also provides the preparation method of the imatinib mesylate M crystal forms, this method can directly obtain the present invention
The imatinib mesylate M crystal forms, technique is simple, mild condition.
The preparation method of imatinib mesylate M crystal forms provided by the invention includes the following steps：Other crystal forms such as α is brilliant
Type or unformed imatinib mesylate are dissolved in polar organic solvent, and 20-60 DEG C of temperature control, preferably 40-50 DEG C, polarity is organic
The preferred methanol of solvent, is optionally added appropriate M crystal forms as crystal seed, crystallization, up to M type imatinib mesylates.
Other crystal forms such as alpha-crystal form or unformed imatinib mesylate are prepared with reference to existing document patent.
The purity of imatinib mesylate M crystal form preparation processes provided by the invention is up to more than 99.7%
The M crystal forms imatinib mesylate of gained of the invention is white to light yellow crystalline powder.
Its dissolubility, method are measured with reference to Chinese Pharmacopoeia two notes on the use of version in 2010：Take this product appropriate, be separately added into each molten
Agent, every strength shaking in 5 minutes 30 seconds, observes the dissolving situation in 30 minutes.It the results are shown in Table 2.It can be seen that the M of present invention gained
Crystalline form imatinib mesylate meets the deliquescent regulation of bulk pharmaceutical chemicals.
2 dissolubility test result of table
Brief description of the drawings
The XRPD figures of imatinib mesylate M crystal form products prepared by 1 embodiment 1 of attached drawing.
Embodiment
Following embodiments are that the present invention is illustrated, and the scope of the present invention should not be construed as limiting.
Embodiment 1：The preparation of imatinib mesylate M crystal forms
The imatinib mesylate 8.0g of alpha-crystal form, methanol 100ml are added in reaction bulb, reaction system is heated to 40 DEG C；Stir
10min is mixed, removes partial solvent under reduced pressure, stirs 10h, filtration drying, obtains white solid 5.32g, purity 99.81%, yield
66.5%, 219-220 DEG C of fusing point.
Embodiment 2：The preparation of imatinib mesylate M crystal forms
The imatinib mesylate 15.0g of alpha-crystal form, methanol 180ml are added in reaction bulb, reaction system is heated to 45 DEG C；
15min is stirred, removes partial solvent under reduced pressure, stirs 12h, filtration drying, obtains white solid 10.4g, purity 99.87%, yield
69.3%, 218-220 DEG C of fusing point.
Embodiment 3：The preparation of imatinib mesylate M crystal forms
Unformed imatinib mesylate 12.0g, methanol 160ml are added in reaction bulb, reaction system is heated to 50 DEG C；
10min is stirred, removes partial solvent under reduced pressure, stirs 15h, filtration drying, obtains white solid 8.17g, purity 99.85%, yield
68.1%, 220-222 DEG C of fusing point.
Embodiment 4：The preparation of imatinib mesylate M crystal forms
The imatinib mesylate 21.0g of alpha-crystal form, methanol 320ml are added in reaction bulb, reaction system is heated to 50 DEG C；
15min is stirred, adds M crystal seed 0.2g, stirs 12h, filtration drying, obtains white solid 18.6g, purity 99.79%, yield
88.5%, 219-220 DEG C of fusing point.
Embodiment 5：The preparation of imatinib mesylate M crystal forms
The imatinib mesylate 25.0g of alpha-crystal form, methanol 250ml are added in reaction bulb, reaction system is heated to 40 DEG C；
15min is stirred, adds M crystal seed 0.3g, stirs 15h, filtration drying, obtains white solid 22.3g, purity 99.80%, yield
89.2%, 217-219 DEG C of fusing point.
Embodiment 6：The preparation of imatinib mesylate M crystal forms
Unformed imatinib mesylate 20.0g, methanol 280ml are added in reaction bulb, reaction system is heated to 40 DEG C；
10min is stirred, adds M crystal seed 0.1g, stirs 15h, filtration drying, obtains white solid 17.6g, purity 99.82%, yield
88.0%, 218-220 DEG C of fusing point.
Embodiment 7：With the contrast test of beta crystal imatinib mesylate
We are using 1 batch of beta crystal of homemade 3 batches of M crystal forms imatinib mesylates and self-control（According to Chinese patent
98807303.X method prepare beta crystal）Imatinib mesylate carries out the comparative study of stability test, detailed comparisons' result
It is shown in Table 3.
30 days comparative test results of table
The result shows that M crystal forms and beta crystal imatinib mesylate, at 0 day, its indices meets the requirements.
Long term test comparing result
Above-mentioned 4 batches of samples are placed in 25 ± 2 DEG C, are placed 24 months under the conditions of relative humidity 60 ± 10%（Commercialized product lattice arrange
The term of validity defended is 24 months, therefore the investigation time is set to 24 months herein）, it is detected by stability high spot reviews project,
It the results are shown in Table 4.
4 long term test comparing result of table
The result shows that：M crystal forms and beta crystal imatinib mesylate, sundry item is without obvious in the experiment of its long-time stability
Difference, but beta crystal imatinib mesylate, genotoxicity impurity T4 is in the term of validity of 24 months apparently higher than M crystal form first sulphurs
Sour Imatinib, does not meet the regulation less than 2ppm,.M crystal form imatinib mesylates, genotoxicity impurity T4 was at 24 months
Still less than 2ppm.
Claims (3)
1. a kind of imatinib mesylate M crystal forms,
It is characterized in that being radiated using Cu-K α, relative intensity exceedes in the powder x-ray diffraction collection of illustrative plates represented with 2 θ angles (°)
2 θ of peak position and relative intensity at 20% 11 peaks are as follows, and the fusing point of M crystal forms is 217-222 DEG C,
The preparation method following steps of the M crystal forms：The imatinib mesylate of other crystal forms is dissolved in polar organic solvent,
At 40-50 DEG C of temperature control, appropriate M crystal forms are optionally added as crystal seed, crystallization, up to M type imatinib mesylates, wherein the machine
Solvent is methanol.
2. imatinib mesylate M crystal forms as claimed in claim 1, it is characterised in that radiated using Cu-K α, with 2 θ angles
The powder x-ray diffraction collection of illustrative plates that (°) represents is as shown in Figure 1.
3. imatinib mesylate M crystal forms as claimed in claim 1, it is characterised in that the methanesulfonic acid of other crystal forms she
Imatinib is alpha-crystal form or unformed.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CO4940418A1 (en) * | 1997-07-18 | 2000-07-24 | Novartis Ag | MODIFICATION OF A CRYSTAL OF A DERIVATIVE OF N-PHENYL-2-PIRIMIDINAMINE, PROCESSES FOR ITS MANUFACTURE AND USE |
-
2014
- 2014-04-09 CN CN201410139481.4A patent/CN104974133B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
Non-Patent Citations (2)
| Title |
|---|
| 甲磺酸伊马替尼的合成;李铭东等;《中国药学杂志》;20080228;第43卷(第3期);228-229页 * |
| 甲磺酸伊马替尼的合成;陈敖等;《精细与专用化学品》;20070421;第15卷(第8期);23-25页 * |
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