CN104817536A - Medicinal imatinib mesylate non-acicular alpha crystal form and preparation method thereof - Google Patents
Medicinal imatinib mesylate non-acicular alpha crystal form and preparation method thereof Download PDFInfo
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- CN104817536A CN104817536A CN201510173028.XA CN201510173028A CN104817536A CN 104817536 A CN104817536 A CN 104817536A CN 201510173028 A CN201510173028 A CN 201510173028A CN 104817536 A CN104817536 A CN 104817536A
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- 0 CC1C=CC(*C(c2ccc(C*3CC*(C)CC3)cc2)=O)=CC1*C(*1)=*C=C[C@@]1C(C=C)=CC=CC Chemical compound CC1C=CC(*C(c2ccc(C*3CC*(C)CC3)cc2)=O)=CC1*C(*1)=*C=C[C@@]1C(C=C)=CC=CC 0.000 description 1
- ABWOUWMKUHHOLA-UHFFFAOYSA-N Cc(ccc(NC(c1ccc(CN2CCN(C)CC2)cc1)OC)c1)c1NC(NC=C1)N=C1c1cnccc1 Chemical compound Cc(ccc(NC(c1ccc(CN2CCN(C)CC2)cc1)OC)c1)c1NC(NC=C1)N=C1c1cnccc1 ABWOUWMKUHHOLA-UHFFFAOYSA-N 0.000 description 1
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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 invention relates to 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino]phenyl]-phenylammonium mesylate as shown in the formula (1), namely an imatinib mesylate non-acicular alpha crystal form, and a preparation method thereof. The non-acicular alpha crystal provided by the invention has good stability and fluidity, is suitable for industrial production, and is very suitable for pharmaceutical preparation application.
Description
Technical field
The present invention relates to the field of chemical synthesis, particularly relate to 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] is amino] phenyl]-aniline mesylate and the non-acicular α crystal formation of imatinib mesylate and preparation method thereof.
Background technology
Imatinib mesylate (imatinib mesylate, trade(brand)name Gleevec) replaces Buddhist nun's class anti-tumor drugs targeting by the first in the world of Novartis Co., Ltd of Switzerland development and production, and U.S. FDA ratifies the listing of this medicine in calendar year 2001.
Current patent report, imatinib mesylate has multiple crystal formation, and known has alpha-crystal form, beta crystal, H1 crystal formation, α 2 crystal formation, I crystal formation, II crystal formation, δ crystal formation, ε crystal formation, F crystal formation, G crystal formation, H crystal form, I crystal and K crystal formation etc.US Patent No. 6894051 discloses two kinds of crystal formations of imatinib mesylate: acicular α crystal formation and non-acicular beta crystal formation, and it is needle-like that this patent refer to gained alpha-crystal form, has and draws moist and poor fluidity, is not suitable for solid pharmaceutical exploitation.Preparation method in addition disclosed in this patent is recrystallization in aqueous ethanolic solution, and cooling obtains; This preparation method's poor stability, is unfavorable for suitability for industrialized production.
Research finds, alpha-crystal form also exists a kind of non-needle-like crystal formation.It is that the non-acicular α crystal formation of 1:1 or 1:2 has without drawing the advantages such as moist and good stability that WO2006048890 mentions a kind of crystal outward appearance long-width ratio, but does not improve liquidity poor shortcoming.It is generally acknowledged, the mobility parameter of crystal formation is the key reference factor whether this crystal formation is suitable for pharmaceutical preparation, and the crystal formation of poor fluidity can cause supplementary material in production process fully to mix, or causes preparation process comparatively difficult.
Therefore, need to develop a kind of good stability, non-acicular α crystal formation in addition with better mobility and preparation method thereof.
Summary of the invention
The object of the invention is to solve the problems of the technologies described above, a kind of good stability is provided, in addition there is certain fluidity, be applicable to non-acicular α crystal formation of pharmaceutical preparation application and preparation method thereof.
The object of the present invention is to provide a kind of non-acicular α crystal formation of imatinib mesylate, the outer shape of described crystal formation is ball-type.
Preferably, the particle diameter d (0.9) >=50 μm of described crystal formation.
Preferably, the particle diameter d (0.5)=15 ~ 50 μm of described crystal formation.
Preferably, the particle diameter d (0.1)≤10 μm of described crystal formation.
Preferably, the bulk density of described crystal formation is not less than 0.2g/cm
3.
Preferably, the slope of repose of described crystal formation is less than 30 °.
Another object of the present invention is also to provide a kind of method preparing described non-acicular α crystal formation, comprises the steps:
The salify in alcohol-halohydrocarbon-water three-phase system by imatinib and methylsulfonic acid, then stirring and crystallizing, separation drying obtain the non-acicular α crystal formation of imatinib mesylate in a solvent.
Preferably, described alcohol is selected from methyl alcohol, ethanol and/or Virahol, more preferably Virahol.
Preferably, described halohydrocarbon is selected from methylene dichloride and/or chloroform, more preferably chloroform.
Preferably, in described three-phase system, the volume ratio of alcohol-halohydrocarbon-water is 10:1 ~ 2:1.
Described alr mode comprises mechanical stirring and ultrasonic oscillation.
Particularly preferred method is, is joined by imatinib in the mixing solutions of Virahol and chloroform, adds methylsulfonic acid and water salify, and wherein the volume ratio of Virahol, chloroform and water is 10:1:1; Use ultrasonic oscillation crystallization, after crystallization is complete, filtration, forced air drying obtain the non-acicular α crystal formation of imatinib mesylate of the present invention.
The invention has the advantages that: by three-phase crystallization system, obtained fast and efficiently and be applicable to medicinal non-acicular α crystal formation, products obtained therefrom yield is high, purity good.The non-acicular α stability of crystal form that present invention process obtains is better, good fluidity, is applicable to suitability for industrialized production, and is very suitable for pharmaceutical preparation application.
Accompanying drawing explanation
Fig. 1 is the microphotograph of the non-acicular α crystal formation of formula 1 compound imatinib mesylate.
Fig. 2 is the microphotograph partial enlarged drawing of the non-acicular α crystal formation of formula 1 compound imatinib mesylate.
Fig. 3 is the x-ray diffraction pattern of the non-acicular α crystal formation of formula 1 compound imatinib mesylate.
Embodiment
Specifically set forth content of the present invention below in conjunction with drawings and Examples, but protection content of the present invention is not defined in specific embodiment.
Embodiment 1
Joined by 18.7g imatinib in 400ml Virahol and 40ml chloroform, mechanical stirring 5 ~ 10min, is heated to 60 ~ 70 DEG C; Add 3.6g methylsulfonic acid and 40ml water, add and continue mechanic whirl-nett reaction 2 ~ 3h, and be cooled to 25 ~ 30 DEG C, filter, gained solid 70 ~ 80 DEG C of forced air drying 6 ~ 7 h, obtain white solid 20.2g, yield: 90.4%, purity: 99.6%.Detect through outward appearance, be the non-acicular α crystal formation of imatinib mesylate in conjunction with XRPD collection of illustrative plates determination gained crystal formation, as shown in Figure 1, its XRPD collection of illustrative plates as shown in Figure 2 for its microphotograph.
Embodiment 2
Joined by 7.2g imatinib in 160ml Virahol and 32ml chloroform, mechanical stirring 5 ~ 10min, is heated to 60 ~ 70 DEG C; Add 1.4g methylsulfonic acid and 16ml water, add and continue mechanic whirl-nett reaction 2 ~ 3h, and be cooled to 25 ~ 30 DEG C, filter, gained solid 70 ~ 80 DEG C of forced air drying 6 ~ 7 h, obtain white solid 7.94g, yield: 92.3%.Detect through outward appearance, can confirm in conjunction with XRPD collection of illustrative plates, products obtained therefrom is non-acicular α crystal formation, is ball-type by microphotograph display gained crystal formation.
Embodiment 3
Be added in 140mL ethanol and 14ml chloroform by 9.8 g imatinib alkali, mechanical stirring 5 ~ 10min, is heated to 60 ~ 70 DEG C, add 1.9g methylsulfonic acid and 14ml water, add and continue mechanic whirl-nett reaction 2 ~ 3h, be cooled to 25 ~ 30 DEG C, filter, gained solid 70 ~ 80 DEG C of forced air drying 6 ~ 7 h, obtain imatinib mesylate salt 10.3g, yield: 88.2%, detect through outward appearance, can confirm in conjunction with XRPD collection of illustrative plates, products obtained therefrom is non-acicular α crystal formation, is ball-type by microphotograph display gained crystal formation.
Embodiment 4
Joined by 18.7g imatinib in 400ml Virahol and 40ml chloroform, ultrasonic oscillation 5 ~ 10min, is heated to 60 ~ 70 DEG C; Add 3.6g methylsulfonic acid and 40ml water, add ultrasonic oscillation reaction 2 ~ 3h, and be cooled to 25 ~ 30 DEG C, filter, gained solid 70 ~ 80 DEG C of forced air drying 6 ~ 7 h, obtain white solid 22.3g, yield: 94.9%, purity: 99.7%.Detect through outward appearance, can confirm in conjunction with XRPD collection of illustrative plates, products obtained therefrom is non-acicular α crystal formation, is ball-type by microphotograph display gained crystal formation.
Data are detected at the granularity of the non-acicular α crystal formation of embodiment 1-4 gained and bulk density, slope of repose
Experimental example 1 stability experiment
INSTRUMENT MODEL: D/Max-RA Japan RigakuX-ray powder diffractometer
Ray: monochromatic Cu-Ka ray (l=1.5418)
Scan mode: q/2q, sweep limit: 3-45
o
Temperature range: 294K voltage: 40KV
X-ray diffraction Data Comparison is in table 2.
By the embodiment of the present invention 1 gained crystal formation temperature 40 DEG C ± 2 DEG C, carry out accelerated stability experiment under relative humidity 75% ± 5% condition, acquired results is as follows:
The X-ray diffraction Data Comparison table of table 2 accelerated stability laboratory sample
Experiment conclusion: after 9 months Acceleration study, x-ray diffraction pattern is consistent with primary data, does not occur to turn brilliant phenomenon, shows that stability of crystal form provided by the present invention is good.
Experimental example 2 stability experiment
Table 3
Experiment conclusion: non-acicular α stability of crystal form provided by the present invention is good.
Claims (12)
1. the non-acicular α crystal formation of formula (1) compound
。
2. the non-acicular α crystal formation of formula according to claim 1 (1) compound, is characterized in that, the outer shape of described crystal formation is ball-type.
3. the non-acicular α crystal formation of formula according to claim 2 (1) compound, is characterized in that, the particle diameter d (0.9) >=50 μm of described crystal formation.
4. the non-acicular α crystal formation of formula according to claim 3 (1) compound, is characterized in that, the particle diameter d (0.5)=15 ~ 50 μm of described crystal formation.
5. the non-acicular α crystal formation of formula (1) compound according to claim 3 and 4, is characterized in that, the particle diameter d (0.1)≤10 μm of described crystal formation.
6. the non-acicular α crystal formation of formula according to claim 1 (1) compound, it is characterized in that, the bulk density of described crystal formation is not less than 0.2g/cm
3.
7. the non-acicular α crystal formation of formula according to claim 1 (1) compound, is characterized in that, the slope of repose of described crystal formation is less than 30 °.
8. prepare the method for the non-acicular α crystal formation of formula (1) compound described in claim 1 ~ 6 any one, described method is with alcohol-halohydrocarbon-water three-phase system crystallization, comprises the following steps:
A, by imatinib and methylsulfonic acid salify;
B, in a solvent stirring and crystallizing;
C, separation drying.
9. preparation method according to claim 7, is characterized in that, described alcohol is selected from methyl alcohol, ethanol and/or Virahol, preferred Virahol.
10. preparation method according to claim 7, is characterized in that, described halohydrocarbon is selected from methylene dichloride and/or chloroform, preferred chloroform.
11. preparation methods according to claim 7, is characterized in that, described stirring comprises mechanical stirring and ultrasonic oscillation.
12. preparation methods according to claim 7, is characterized in that, the volume ratio of described alcohol-halohydrocarbon-water is 10:1 ~ 2:1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510173028.XA CN104817536A (en) | 2015-04-14 | 2015-04-14 | Medicinal imatinib mesylate non-acicular alpha crystal form and preparation method thereof |
| CN201610911948.1A CN106518844A (en) | 2015-04-14 | 2015-04-14 | An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105399724A (en) * | 2015-11-05 | 2016-03-16 | 齐鲁天和惠世制药有限公司 | Preparation method of non-acicular alpha crystal form imatinib mesylate |
| CN105566291A (en) * | 2016-02-02 | 2016-05-11 | 连云港恒运医药科技有限公司 | Method for preparing methanesulfonic acid imatinib crystal form |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957206B (en) * | 2022-04-11 | 2024-02-27 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006048890A1 (en) * | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
| CN103570673A (en) * | 2012-08-04 | 2014-02-12 | 浙江九洲药业股份有限公司 | Preparation method of imatinib mesylate alpha crystal form |
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 |
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2015
- 2015-04-14 CN CN201510173028.XA patent/CN104817536A/en active Pending
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006048890A1 (en) * | 2004-11-04 | 2006-05-11 | Sun Pharmaceutical Industries Limited | Imatinib mesylate crystal form and process for preparation thereof |
| CN103570673A (en) * | 2012-08-04 | 2014-02-12 | 浙江九洲药业股份有限公司 | Preparation method of imatinib mesylate alpha crystal form |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105399724A (en) * | 2015-11-05 | 2016-03-16 | 齐鲁天和惠世制药有限公司 | Preparation method of non-acicular alpha crystal form imatinib mesylate |
| CN105566291A (en) * | 2016-02-02 | 2016-05-11 | 连云港恒运医药科技有限公司 | Method for preparing methanesulfonic acid imatinib crystal form |
| CN105566291B (en) * | 2016-02-02 | 2018-06-01 | 连云港恒运药业有限公司 | The method for preparing Crystal form of imatinib mesylate |
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| CN106518844A (en) | 2017-03-22 |
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Address after: 222047 tenth Industrial Zone, Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: JIANGSU HANSOH PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222047 tenth Industrial Zone, Lianyungang economic and Technological Development Zone, Jiangsu Applicant before: Jiangsu best Pharmaceutical Co.,Ltd. Address after: 222047 tenth Industrial Zone, Lianyungang economic and Technological Development Zone, Jiangsu Applicant after: Jiangsu best Pharmaceutical Co.,Ltd. Address before: 222047 tenth Industrial Zone, Lianyungang economic and Technological Development Zone, Jiangsu Applicant before: JIANGSU HANSOH PHARMACEUTICAL Co.,Ltd. |
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