CN109020954A - A kind of nilotinib novel crystal forms - Google Patents
A kind of nilotinib novel crystal forms Download PDFInfo
- Publication number
- CN109020954A CN109020954A CN201810744947.1A CN201810744947A CN109020954A CN 109020954 A CN109020954 A CN 109020954A CN 201810744947 A CN201810744947 A CN 201810744947A CN 109020954 A CN109020954 A CN 109020954A
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- China
- Prior art keywords
- nilotinib
- preparation
- crystal forms
- novel crystal
- ethanol water
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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
- C07D401/14—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 three or more hetero rings
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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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of novel crystal forms of nilotinib, belong to bulk pharmaceutical chemicals preparation technical field.The technical scheme is that a kind of nilotinib novel crystal forms, at 6.76,7.44 °, 12.86 °, 13.48 °, 16.71 °, 19.72,21.85 °, 22.89 °, 25.98 °, 26.86 °, 29.24 ° of diffraction angular positions have characteristic peak.The present invention provides a kind of nilotinib novel crystallizations, substantially increase the solubility of bulk pharmaceutical chemicals.
Description
Technical field
The present invention relates to a kind of novel crystal forms of nilotinib, belong to bulk pharmaceutical chemicals preparation technical field.
Background technique
Nilotinib is antineoplastic, and it is thin to the drug resistant chronic grain of Gleevec (Imatinib) to be clinically mainly used for treatment
Born of the same parents' property leukaemia.For potent accurately second generation tyrosine kinase inhibitor, effectively treatment is generated drug resistant or is not tolerated slow
Property myelogenous leukemia patient.
Nilotinib belongs to insoluble drugs, and solubility 0.2ug/ ml, Yuan Yan Novartis Co., Ltd in water is to guarantee
Bioavilability carries out micronization processes using by nilotinib, to increase the dissolution of main ingredient.But the process meeting of micronization
Cause the pollution of environment.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of nilotinib novel crystal forms of higher solubility, mention for preparation
For quality raw materials medicine.
The technical scheme is that a kind of nilotinib novel crystal forms, at 6.76,7.44 °, 12.86 °, 13.48 °,
16.71 °, 19.72,21.85 °, 22.89 °, 25.98 °, 26.86 °, 29.24 ° of diffraction angular positions have characteristic peak.
The preparation method of nilotinib novel crystal forms of the present invention, prepares according to the following steps:
Nilotinib is dissolved in acetone by the first step；Concentration range is prepared as 0.14g/ml to 0.22g/ml solution；
The active carbon of first step nilotinib weight 1/10th is added into first step solution for second step, and acetic acid is added in stirring
The dehydrated alcohol of ethyl ester volume 1/10th, filtering；
Filtrate obtained by second step is cooled to -20 DEG C to -15 DEG C ranges and maintained by third step, and stirring flows down plus first step solvent
1.4-2.5 times of volume of 50-60% ethanol water；Mixing speed is 300-380 revs/min, and the speed of stream plus ethanol water is
8-12ml/ points, after stream adds, continue stirring 4-6 hours；
The filtering of 4th step, washs filter cake with 50-60% ethanol water, dries.
Preferably, first step acquired solution concentration is 0.16-0.20g/ml solution.
Preferably, second step crystallization temperature is -18 DEG C to -16 DEG C；The concentration of ethanol water is 55%；Stream plus ethanol water
The speed of solution is 9-10ml/ points.
The utility model has the advantages that solubility can achieve 0.36 ug/ ml the present invention provides a kind of nilotinib novel crystallization,
The solubility of bulk pharmaceutical chemicals is substantially increased, the bulk pharmaceutical chemicals that can directly use is provided for nilotinib preparation, eliminates micro mist
Change program, while improving dissolution rate, provides good working environment for preparation worker.
The X powder diffraction figure of Fig. 1 product of the embodiment of the present invention.
The embodiment embodiment of the present invention uses the crude product of prior art preparation with nilotinib, and HPLC detection level is
95.74%。
Embodiment 1.
14g nilotinib is dissolved in 100ml ethyl acetate by the first step, and preparation concentration is 0.14g/ml solution；
1g active carbon is added into first step solution for second step, stirring, and 10ml dehydrated alcohol, filtering is added；
Filtrate obtained by second step is cooled to -20 DEG C and maintained by third step, and stirring flows down plus 50% ethanol water of 140ml；It stirs
Mixing speed is 300 revs/min, speed 8ml/ points of stream plus ethanol water, after stream adds, continues stirring 4 hours；
The filtering of 4th step, washs filter cake with 50% ethanol water, dries, and obtains nilotinib fine work, and HPLC detection purity is
99.42%, yield 92.08%, D90 is 38.6 microns, and X-ray powder diffraction figure is shown in attached drawing 1.
Embodiment 2.
22g nilotinib is dissolved in 100ml ethyl acetate by the first step；Preparation concentration is 0.22g/ml solution；
1g active carbon is added into first step solution for second step, stirring, and 10ml dehydrated alcohol, filtering is added；
Filtrate obtained by second step is cooled to -15 DEG C and maintained by third step, and stirring flows down plus 60% ethanol water of 250ml；It stirs
Mixing speed is 380 revs/min, and the speed of stream plus ethanol water is 12ml/ points, after stream adds, continues stirring 6 hours；
The filtering of 4th step, washs filter cake with 60% ethanol water, dries, and obtains nilotinib fine work, and HPLC detection purity is
99.78%, yield 92.39%, D90 is 24.82 microns, and X-ray powder diffraction figure is shown in attached drawing 1.
Embodiment 3
18g nilotinib is dissolved in 100ml ethyl acetate by the first step；Preparation concentration is 0.18g/ml solution；
1g active carbon is added into first step solution for second step, stirring, and 10ml dehydrated alcohol, filtering is added；
Filtrate obtained by second step is cooled to -18 DEG C and maintained by third step, and stirring flows down plus 55% ethanol water of 200ml；It stirs
Mixing speed is 348 revs/min, and the speed of stream plus ethanol water is 10ml/ points, after stream adds, continues stirring 5 hours；
The filtering of 4th step, washs filter cake with 55% ethanol water, dries, and obtains nilotinib fine work, and HPLC detection purity is
99.88%, yield 93.48%, D90 is 30.21 microns, and X-ray powder diffraction figure is shown in attached drawing 1.
Test example 1. is measured the solubility of room temperature Example 1-3, data by the solubility test method of States Pharmacopoeia specifications respectively
It is recorded in table 1.
Table 1
| 1 product of embodiment | 2 product of embodiment | 3 product of embodiment | |
| Solubility, ug/ ml | 0.34 | 0.36 | 0.35 |
1 data of table explanation, product solubility of the embodiment of the present invention are greatly improved.
Test example 2 distinguishes each 20 grams of product of Example 1-3, is laid in surface plate, is placed in climatic chamber,
40 DEG C, relative humidity 75% is stored 30 days, is taken out, and measures content respectively, in relation to substance and X-ray powder diffraction.Data record
In table 2.
Table 2
2 data of table illustrate that product of the embodiment of the present invention is stable under high temperature, super-humid conditions.
Claims (7)
1. a kind of nilotinib novel crystal forms, characterized in that at 6.76,7.44 °, 12.86 °, 13.48 °, 16.71 °, 19.72,
21.85 °, 22.89 °, 25.98 °, 26.86 °, 29.24 ° of diffraction angular positions have characteristic peak.
2. the preparation method of nilotinib novel crystal forms described in claim 1, characterized in that prepare according to the following steps:
Nilotinib is dissolved in acetone by the first step；
The active carbon of first step nilotinib weight 1/10th is added into first step solution for second step, and acetic acid is added in stirring
The dehydrated alcohol of ethyl ester volume 1/10th, filtering；
Filtrate obtained by second step is cooled to -20 DEG C to -15 DEG C ranges and maintained by third step, and stirring flows down plus first step solvent
1.4-2.5 times of volume of 50-60% ethanol water；Mixing speed is 300-380 revs/min, and the speed of stream plus ethanol water is
8-12ml/ points, after stream adds, continue stirring 4-6 hours；
The filtering of 4th step, washs filter cake with 50-60% ethanol water, dries.
3. the preparation method of nilotinib novel crystal forms according to claim 2, characterized in that the solution concentration of first step preparation
Range is 0.14g/ml to 0.22g/ml.
4. the preparation method of nilotinib novel crystal forms according to claim 2, characterized in that the solution concentration of first step preparation
For 0.16-0.20g/ml.
5. the preparation method of nilotinib novel crystal forms according to claim 2, characterized in that second step crystallization temperature is -18
DEG C to -16 DEG C.
6. the preparation method of nilotinib novel crystal forms according to claim 2, characterized in that second step ethanol water it is dense
Degree is 55%.
7. the preparation method of nilotinib novel crystal forms according to claim 2, characterized in that second step stream adds ethanol water
Speed be 9-10ml/ point.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810744947.1A CN109020954A (en) | 2018-07-09 | 2018-07-09 | A kind of nilotinib novel crystal forms |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810744947.1A CN109020954A (en) | 2018-07-09 | 2018-07-09 | A kind of nilotinib novel crystal forms |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109020954A true CN109020954A (en) | 2018-12-18 |
Family
ID=64641894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810744947.1A Withdrawn CN109020954A (en) | 2018-07-09 | 2018-07-09 | A kind of nilotinib novel crystal forms |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109020954A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939945A (en) * | 2021-02-25 | 2021-06-11 | 深圳市泰力生物医药有限公司 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
| CN116102540A (en) * | 2023-01-05 | 2023-05-12 | 浙江工业大学 | Novel two nilotinib free base crystal forms and preparation method thereof |
-
2018
- 2018-07-09 CN CN201810744947.1A patent/CN109020954A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112939945A (en) * | 2021-02-25 | 2021-06-11 | 深圳市泰力生物医药有限公司 | Crystalline forms of nilotinib, active drugs and pharmaceutical compositions prepared using the crystalline forms |
| CN116102540A (en) * | 2023-01-05 | 2023-05-12 | 浙江工业大学 | Novel two nilotinib free base crystal forms and preparation method thereof |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20181218 |
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| WW01 | Invention patent application withdrawn after publication |