CN106518844A - An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof - Google Patents
An imatinib mesylate crystal form suitable for officinal uses and a preparing method thereof Download PDFInfo
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- CN106518844A CN106518844A CN201610911948.1A CN201610911948A CN106518844A CN 106518844 A CN106518844 A CN 106518844A CN 201610911948 A CN201610911948 A CN 201610911948A CN 106518844 A CN106518844 A CN 106518844A
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- needle
- crystal form
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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
Abstract
The invention relates to 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-phenyl]phenylamine mesylate shown as a formula (1), namely an imatinib mesylate non-needle alpha crystal form, and a preparing method thereof. The non-needle alpha crystal form is good in stability and fluidity, suitable for industrial production and particularly suitable for medical preparations.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to 4- [(4- methyl isophthalic acids-piperazine) methyl]-N- [4- methyl -3-
[[4- (3- pyridines) -2- pyrimidines] amino] phenyl]-aniline mesylate is the non-needle-like alpha-crystal form of imatinib mesylate and its system
Preparation Method.
Background technology
Imatinib mesylate (imatinib mesylate, trade name Gleevec) is to be developed to give birth to by Novartis Co., Ltd of Switzerland
That what is produced is first in the world for Buddhist nun's class anti-tumor drugs targeting, and U.S. FDA is ratified the medicine and listed in calendar year 2001.
Current patent report, imatinib mesylate have various crystal formations, it is known that have alpha-crystal form, beta crystal, H1 crystal formations, α 2
Crystal formation, I crystal formation, II crystal formation, δ crystal formations, ε crystal formations, F crystal formations, G crystal formations, H crystal form, I crystal and K crystal formations etc..United States Patent (USP)
US6894051 discloses two kinds of crystal formations of imatinib mesylate：Needle-like alpha-crystal form and non-needle-like beta crystal, the patent refer to institute
It is needle-like to obtain alpha-crystal form, has and draws moist and poor fluidity, is not suitable for solid drugs exploitation.The other preparation side disclosed in patent
Method is recrystallized in ethanol water, and cooling is obtained；The preparation method stability is poor, is unfavorable for industrialized production.
Research finds that alpha-crystal form also has a kind of non-needle-like crystal formation.WO2006048890 mentions a kind of crystal outward appearance length-width ratio
For 1:1 or 1:2 non-needle-like alpha-crystal form has the advantages that nothing draws moist and good stability, but improves poor fluidity
Shortcoming.It is generally believed that the mobility parameter of crystal formation is the crystal formation key reference factor of pharmaceutical preparation whether is suitable for, flowing
Property difference crystal formation can cause production process in supplementary material cannot be sufficiently mixed, or cause preparation process more difficult.
Accordingly, it would be desirable to a kind of good stability is developed, the non-needle-like alpha-crystal form and its preparation side also with preferable mobility
Method.
The content of the invention
It is an object of the invention to solve above-mentioned technical problem, there is provided a kind of good stability, also with certain fluidity,
Non- needle-like alpha-crystal form of suitable pharmaceutical preparation application and preparation method thereof.
It is an object of the invention to provide a kind of non-needle-like alpha-crystal form of imatinib mesylate, the outside shape of the crystal formation
Shape is ball-type.
Preferably, the particle diameter d (0.9) >=50 μm of the crystal formation.
Preferably, the particle diameter d (0.5)=15～50 μm of the crystal formation.
Preferably, the particle diameter d (0.1)≤10 μm of the crystal formation.
Preferably, the heap density of the crystal formation is not less than 0.2g/cm3。
Preferably, the angle of repose of the crystal formation is less than 30 °.
Another object of the present invention also resides in a kind of method for preparing the non-needle-like alpha-crystal form of offer, comprises the steps：
By Imatinib and methanesulfonic acid in alcohol-halogenated hydrocarbons-water three-phase system into salt, then stirring and crystallizing, separation in a solvent
It is dried to obtain the non-needle-like alpha-crystal form of imatinib mesylate.
Preferably, described alcohol is selected from methyl alcohol, ethanol and/or isopropanol, more preferably isopropanol.
Preferably, described halogenated hydrocarbons is selected from dichloromethane and/or chloroform, more preferably chloroform.
Preferably, in the three-phase system, the volume ratio of alcohol-halogenated hydrocarbons-water is 10：1～2：1.
Described agitating mode includes mechanical agitation and ultrasonic oscillation.
Particularly preferred method is that Imatinib is added in the mixed solution of isopropanol and chloroform, adds methanesulfonic acid
With water into salt, the wherein volume ratio of isopropanol, chloroform and water is 10:1:1；Use ultrasonic oscillation crystallization, after crystallization is complete, mistake
Filter, forced air drying obtain the non-needle-like alpha-crystal form of imatinib mesylate of the present invention.
The invention has the advantages that：By three-phase crystallization system, fast and efficiently it has been obtained and has been adapted to medicinal non-acicular α crystalline substance
Type, products obtained therefrom high income, purity are good.Non- acicular α stability of crystal form obtained in present invention process is preferable, good fluidity, is adapted to
Industrialized production, and it is very suitable for pharmaceutical preparation application.
Description of the drawings
Fig. 1 is the microphotograph of the non-needle-like alpha-crystal form of 1 compound imatinib mesylate of formula.
Fig. 2 is the microphotograph partial enlarged drawing of the non-needle-like alpha-crystal form of 1 compound imatinib mesylate of formula.
Fig. 3 is the x-ray diffraction pattern of the non-needle-like alpha-crystal form of 1 compound imatinib mesylate of formula.
Specific embodiment
Present disclosure is specifically described below in conjunction with drawings and Examples, but the protection content of the present invention is not limited
Due to specific embodiment.
Embodiment 1
18.7g Imatinibs are added in 400ml isopropanols and 40ml chloroforms, 5～10min of mechanical agitation, it is heated to 60～
70℃；3.6g methanesulfonic acids and 40ml water is added, continuation 2～3h of mechanic whirl-nett reaction is added, and is cooled to 25～30 DEG C, filter,
Gained 70～80 DEG C of 6～7h of forced air drying of solid, obtain white solid 20.2g, yield：90.4%, purity：99.6%.Jing outward appearances
Detection, determines gained crystal formation for the non-needle-like alpha-crystal form of imatinib mesylate with reference to XRPD collection of illustrative plates, its microphotograph such as Fig. 1 institutes
Show, its XRPD collection of illustrative plates is as shown in Figure 2.
Embodiment 2
7.2g Imatinibs are added in 160ml isopropanols and 32ml chloroforms, 5～10min of mechanical agitation is heated to 60～70
℃；1.4g methanesulfonic acids and 16ml water is added, continuation 2～3h of mechanic whirl-nett reaction is added, and is cooled to 25～30 DEG C, filter, institute
70～80 DEG C of 6～7h of forced air drying of solid are obtained, white solid 7.94g, yield is obtained：92.3%.Jing outward appearances are detected, are schemed with reference to XRPD
Spectrum it has been confirmed that products obtained therefrom be non-needle-like alpha-crystal form, as obtained by microphotograph shows crystal formation be ball-type.
Embodiment 3
9.8g Imatinib alkali is added in 140mL ethanol and 14ml chloroforms, 5～10min of mechanical agitation is heated to 60～70
DEG C, 1.9g methanesulfonic acids and 14ml water is added, continuation 2～3h of mechanic whirl-nett reaction is added, is cooled to 25～30 DEG C, filter, gained
70～80 DEG C of 6～7h of forced air drying of solid, obtain imatinib mesylate salt 10.3g, yield：88.2%, Jing outward appearance is detected, is tied
Close XRPD collection of illustrative plates it has been confirmed that products obtained therefrom be non-needle-like alpha-crystal form, as obtained by microphotograph shows crystal formation be ball-type.
Embodiment 4
18.7g Imatinibs are added in 400ml isopropanols and 40ml chloroforms, 5～10min of ultrasonic oscillation is heated to 60
～70 DEG C；3.6g methanesulfonic acids and 40ml water is added, ultrasonic oscillation is added and is reacted 2～3h, and be cooled to 25～30 DEG C, filter,
Gained 70～80 DEG C of 6～7h of forced air drying of solid, obtain white solid 22.3g, yield：94.9%, purity：99.7%.Jing outward appearances
Detection, with reference to XRPD collection of illustrative plates it has been confirmed that products obtained therefrom is non-needle-like alpha-crystal form, as obtained by microphotograph shows, crystal formation is
Ball-type.
The granularity and heap density of non-needle-like alpha-crystal form obtained by embodiment 1-4, angle of repose detection data
1 stability experiment of experimental example
INSTRUMENT MODEL：D/Max-RA Japan RigakuX- ray powder diffractometers
Ray：Monochromatic Cu-Ka rays
Scan mode：Q/2q, sweep limits：3-45 °
Temperature range：294K voltages：40KV
X-ray diffraction Data Comparison is shown in Table 2.
By 1 gained crystal formation of the embodiment of the present invention in 40 DEG C ± 2 DEG C of temperature, carry out under the conditions of relative humidity 75% ± 5% plus
Fast stability experiment, acquired results are as follows：
The X-ray diffraction Data Comparison table of 2 accelerated stability laboratory sample of table
Experiment conclusion：After 9 months Acceleration studies, x-ray diffraction pattern is consistent with primary data, turns a brilliant phenomenon, table without generation
Bright stability of crystal form provided by the present invention is good.
2 stability experiment of experimental example
Table 3
Experiment conclusion：Non- acicular α stability of crystal form provided by the present invention is good.
Claims (12)
1. formula（1）The non-needle-like alpha-crystal form of compound
。
2. formula according to claim 1（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the outer shape of the crystal formation
It is ball-type.
3. formula according to claim 2（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the particle diameter d of the crystal formation
(0.9)≥50μm。
4. formula according to claim 3（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the particle diameter d of the crystal formation
(0.5)=15~50μm。
5. the formula according to claim 3 and 4（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the particle diameter d of the crystal formation
(0.1)≤10μm。
6. formula according to claim 1（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the heap density of the crystal formation is not
Less than 0.2g/cm3。
7. formula according to claim 1（1）The non-needle-like alpha-crystal form of compound, it is characterised in that the angle of repose of the crystal formation is little
In 30 °.
8. formula described in claim 1 ~ 6 any one is prepared（1）The method of the non-needle-like alpha-crystal form of compound, methods described be with alcohol-
Halogenated hydrocarbons-water three-phase system crystallization, comprises the following steps：
A, by Imatinib with methanesulfonic acid into salt；
B, in a solvent stirring and crystallizing；
C, separation drying.
9. preparation method according to claim 7, it is characterised in that the alcohol is selected from methyl alcohol, ethanol and/or isopropanol,
It is preferred that isopropanol.
10. preparation method according to claim 7, it is characterised in that the halogenated hydrocarbons is selected from dichloromethane and/or chlorine
Imitate, preferably chloroform.
11. preparation methods according to claim 7, it is characterised in that the stirring includes mechanical agitation and ultrasonic wave shake
Swing.
12. preparation methods according to claim 7, it is characterised in that the volume ratio of the alcohol-halogenated hydrocarbons-water is 10：1~
2：1.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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|---|---|---|---|
| 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 (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957206A (en) * | 2022-04-11 | 2022-08-30 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
Families Citing this family (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 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
-
2015
- 2015-04-14 CN CN201610911948.1A patent/CN106518844A/en active Pending
- 2015-04-14 CN CN201510173028.XA patent/CN104817536A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 平其能 等: "《现代药剂学》", 31 October 1998 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114957206A (en) * | 2022-04-11 | 2022-08-30 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
| CN114957206B (en) * | 2022-04-11 | 2024-02-27 | 中国药科大学 | Imatinib eutectic crystal and preparation method thereof |
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| CN104817536A (en) | 2015-08-05 |
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Application publication date: 20170322 |