CN109516991A - A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof - Google Patents
A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof Download PDFInfo
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- CN109516991A CN109516991A CN201811644015.6A CN201811644015A CN109516991A CN 109516991 A CN109516991 A CN 109516991A CN 201811644015 A CN201811644015 A CN 201811644015A CN 109516991 A CN109516991 A CN 109516991A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to pharmaceutical technology field, a kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof is disclosed.The X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement is as shown in Figure 1, its X-ray powder diffraction collection indicated with the 2 θ ± 0.2 ° angles of diffraction shows characteristic diffraction peak at 3.71 °, 6.57 °, 10.88 °, 13.21 °, 15.09 °, 16.87 °, 20.01 °, 21.22 °, 25.47 °, 26.07 °, 27.69 °, 31.03 °, 32.02 °, 33.18 ° and 36.74 °.Content of the citric acid tropsch imatinib crystal form provided by the invention under high temperature, high humidity, illumination condition in relation to substance is substantially unchanged, crystal form property is stablized, the crystal form that this method obtains has preferable dissolubility and mobility, it is readily transported storage, and operating method is simple, suitable industrialized production, high income, purity are good.
Description
Technical field
The present invention relates to a kind of citric acid tropsch imatinib crystal-form compounds and preparation method thereof, belong to pharmaceutical technology field.
Background technique
Citric acid tropsch imatinib (Tofacitinib citrate), molecular structural formula is such as shown in (I):
Tropsch imatinib (Tofacitinib) is a kind of new oral JAK pathway inhibitor of Pfizer's research and development.With it is current
Extracellular target spot is mainly acted on unlike other most RA therapeutic agents, tropsch imatinib is with intracellular signal transduction access
Target spot acts on the core of cytokine network.Tropsch imatinib (tofacitinib) is pair to the inhibition strength of JAK3
5~100 times of JAK1 and JAK2.Tropsch imatinib is the pioneering drug that exploitation is used for rheumatoid arthritis treatment, and FDA is in 2012
JAK inhibitor tofacitinib is had approved on November 6, in for treating the activities of adults phase and reacting not methotrexate (MTX) (MTX)
To severe rheumatoid arthritis (RA) patient in good.
FDA indicate, in arrive severe rheumatoid arthritis people, can not be from conventional oral treatment drug methotrexate
(methotrexate) when benefiting in or can not be resistance to treated, the new drug Xeljanz (tropsch imatinib) of Pfizer can be used.Support method is replaced
Buddhist nun can be applied alone, and can also share with methotrexate (MTX) and other specific standard care drugs.FDA ratifies Xeljanz twice a day, often
Secondary 5 milligrams of dosage.
Patent CN 201610817563.9 provides a kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form, will
Citric acid is dissolved in the in the mixed solvent of organic solvent and water, or citric acid is dissolved in water, and obtains citric acid soln；It will
Tropsch imatinib is dissolved in the in the mixed solvent of organic solvent and water, and heating obtains tropsch imatinib solution；In a heated condition, Chinese holly
Rafter acid solution and tropsch imatinib solution hybrid reaction；Crystal form is dried to obtain in cooling, separating obtained solid.Using elder generation at salt again
The operating method of recrystallization.
Patent CN 201410740110.1 provides a kind of preparation method of medicinal crystal-form citric acid tropsch imatinib, takes Chinese holly
Rafter acid tropsch imatinib bulk pharmaceutical chemicals, vacuum are pumped into solvent, and heating makes it dissolve simultaneously insulated and stirred 1~2 hour；Slow cooling to 0~
50 DEG C, stir 4~10 hours crystallizations；Filtering, drying are to get medicinal crystal-form citric acid tropsch imatinib, and yield reaches 90%, finished product
For stable crystal form.
Patent CN 201310046162.4 provides a kind of preparation method of amorphous tofacitinib citrate, the preparation
Method is easy, comprising the following steps: 30-50 DEG C of range at a temperature of, formed with organic solvent dissolution citric acid tropsch imatinib
The solution is added in 15-25 DEG C of water to be formed and precipitate, it is small which is placed on 4-24 in 15-25 DEG C of environment by solution
When, then recycle amorphous tofacitinib citrate.
A kind of tropsch imatinib hydrate of patent CN 201310419942.9 and preparation method thereof, is related to 3- { (3R, 4R) -4-
Methyl -3- [methyl-(7H- pyrrolo- [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl } one citric acid of -3- oxo-propionitrile
Two hydrate crystal of salt and preparation method thereof include characteristic peaks shown in the angle following 2 θ in X-ray diffraction spectrogram:
6.54°、7.22°、7.94°、8.70°、10.92°、11.77°、12.32°、13.12°、14.44°、15.76°、16.57°、
17.28°、18.12°、18.86°。
A kind of support of patent CN 201310419728.3 replaces Buddhist nun's compound, is related to 3- { (3R, 4R) -4- methyl -3- [methyl -
(7H- pyrrolo- [2,3-d] pyrimidine-4-yl)-amino]-piperidin-1-yl -3- oxo-propionitrile one citrate a hydrate
Object crystal and preparation method thereof includes characteristic peaks shown in the angle following 2 θ in X-ray diffraction spectrogram: 5.81 °, 6.92 °,
7.74°、8.30°、10.10°、10.51°、10.90°、11.34°、12.57°、13.65°、14.47°、15.14°、16.93°。
It is known by a person skilled in the art that polymorph in pharmaceuticals is an important factor for influencing drug quality, to the physics and chemistry of drug
Property, bioavilability, related preparations quality etc. all have a major impact, at present pass of such phenomenon by pharmacy worker
Note, it is clear that have become one of content indispensable in drug research and drug quality control.It is same due to different crystal forms
One drug solubility, mobility, fusing point, density, hardness, appearance and in terms of there were significant differences, thus
The performance of the stability, bioavilability and curative effect of drug is influenced, research citric acid tropsch imatinib novel crystal forms are next step citron
The medicinal property of sour tropsch imatinib, improves its bioavilability, has great importance for its clinical application.
Summary of the invention
Primary goal of the invention of the invention is to propose a kind of citric acid tropsch imatinib crystal-form compound and its preparation side
Method, the present invention provides a kind of new crystalline form of formula (I) compound, this method is easy to operate, high income, favorable reproducibility, crystal form
Purity is high.
In order to achieve the object of the present invention, the technical solution of use are as follows:
The present invention provides a kind of citric acid tropsch imatinib crystal-form compound, it is characterised in that: it is with the 2 θ ± 0.2 ° angles of diffraction
The X-ray powder diffraction collection of expression 3.71 °, 6.57 °, 10.88 °, 13.21 °, 15.09 °, 16.87 °, 20.01 °,
Characteristic diffraction peak is shown at 21.22 °, 25.47 °, 26.07 °, 27.69 °, 31.03 °, 32.02 °, 33.18 ° and 36.74 °.
The X-ray powder that citric acid tropsch imatinib crystal-form compound provided by the invention is obtained using Cu-K alpha ray measurement
Diffraction pattern is as shown in Figure 1.
The preparation method of citric acid tropsch imatinib crystal-form compound provided by the invention, includes the following steps:
(1) solvent A is poured into citric acid tropsch imatinib crude product, is heated until the temperature is raised to dissolve, solvent B, heating are added later
To 85 DEG C of 30~60min of stirring；
(2) active carbon decoloring is added, continues to stir 30min, filter while hot；
(3) 0~5 DEG C of the solvent C that filtrate obtained above is continued to agitation and dropping pre-cooling, with the dropping temperature of solvent
It constantly is reduced to out crystalline substance, program is cooled to -10 DEG C~-5 DEG C, precipitates crystal, and insulated and stirred is complete to crystallization；
(4) it filters, washing is dried in vacuo crystal, obtains the crystallization of citric acid tropsch imatinib.
Preferably, in step (1), the solvent A is dimethylformamide, n-butanol, dimethyl sulfoxide or acetonitrile；
Solvent B is ethyl acetate, methyl tertiary butyl ether(MTBE) or ether；The mass volume ratio of citric acid tropsch imatinib crude product and solvent A is 1:
0.5~3g/ml.
Preferably, in step (2), the quality of active carbon is the 3%~5% of citric acid tropsch imatinib crude product quality.
Preferably, in step (3), the solvent C is methylene chloride, petroleum ether or n-hexane；Solvent A, solvent B
Volume ratio with solvent C is 1:1~5:1~5.5；Program cooling dropped 1 DEG C~2 DEG C for every 15 minutes, was down to -10 DEG C~-5 DEG C,
The crystallization time is 5~12h, and mixing speed is 10~15 revs/min.
Preferably, in step (4), vacuum drying refers to 5~10h of vacuum drying at 40~50 DEG C.
Compared with prior art, the present invention has the advantage that
(1) citric acid tropsch imatinib crystal-form compound provided by the present invention is a kind of new crystalline substance different from the prior art
Type；Preparation method is simple to operation, and reaction condition is mild, is suitble to industrialized production.
(2) present invention has carried out influence factor test and long term test research to citric acid tropsch imatinib crystal-form compound,
Wherein largest single impurity is not obviously increased with always miscellaneous, and indices have no significant change, and illustrate that citric acid tropsch imatinib is order
Close that object is with good stability, reproducibility, transfer, storage, operation, clinical application are safer in technique easy to produce.
(3) citric acid tropsch imatinib crystal form provided by the present invention is that the preparation of subsequent related preparations improves medicine well
The solubility of object in water, improves effective bioavilability.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction collection of citric acid tropsch imatinib crystal-form compound prepared by the embodiment of the present invention 1.
Fig. 2 is the TG-DSC map of citric acid tropsch imatinib crystal-form compound prepared by the embodiment of the present invention 1.
Specific embodiment
Technical solution of the present invention is described in detail with embodiment below, it will help to technical solution of the present invention
The advantages of, effect have further understanding, the scope of protection of the present invention is not limited for embodiment, and protection scope of the present invention is by weighing
Benefit requires to determine.
Citric acid tropsch imatinib crude product is using embodiment method in patent CN201610240571.1 in the embodiment of the present invention
Preparation.
Embodiment 1: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 25ml dimethylformamide is added in reaction flask, is heated to molten
Solution, adds ethyl acetate 25ml, continues to be heated to 85 DEG C, stirs 30min；
(2) active carbon 1.5g is added, continues stirring 30 minutes, filters while hot；
(3) by 0 DEG C of dichloromethane solution 25ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly drops
It is low, it is added dropwise, continues to be cooled to -5 DEG C (cooling extent is to drop 1 DEG C in every 15 minutes), 10 revs/min of mixing speed, stirring analysis
Brilliant 5h；
(4) it filters, filter cake obtains 49.7g white solid, yield 99.4%, largest single impurity in 40 DEG C of vacuum drying 5h
0.01%, purity 99.98% (HPLC detection).
Embodiment 2: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 150ml n-butanol is added in reaction flask, is heated until the temperature is raised to dissolve, then
750ml methyl tertiary butyl ether(MTBE) is added, continues to be heated to 85 DEG C, stirs 40min；
(2) active carbon 2.5g is added, continues stirring 30 minutes, filters while hot；
(3) it by 5 DEG C of petroleum ether 825ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly reduces, is added dropwise
After, continue to be cooled to -10 DEG C (cooling extent is to drop 2 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring and crystallizing
12h；
(4) it filters, filter cake obtains 49.7g white solid, yield 99.5%, largest single impurity in 50 DEG C of vacuum drying 10h
0.01%, purity 99.98% (HPLC detection).
Embodiment 3: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 50ml dimethyl sulfoxide is added in reaction flask, is heated to molten
Solution, adds 100ml ether, continues to be heated to 85 DEG C, stirs 50min；
(2) active carbon 2g is added, continues stirring 30 minutes, filters while hot；
(3) it by 3 DEG C of n-hexane 150ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly reduces, is added dropwise
After, continue to be cooled to -8 DEG C (cooling extent is to drop 2 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring and crystallizing 10h；
(4) it filters, filter cake obtains 49.7g white solid, yield 99.5%, largest single impurity in 45 DEG C of vacuum drying 8h
0.02%, purity 99.99% (HPLC detection).
Embodiment 4: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 100ml acetonitrile is added in reaction flask, is heated until the temperature is raised to dissolve, then plus
Enter 500ml ethyl acetate, continues to be heated to 85 DEG C, stir 40min；
(2) active carbon 2g is added, continues stirring 30 minutes, filters while hot；
(3) it by 2 DEG C of petroleum ether 200ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly reduces, is added dropwise
After, continue to be cooled to -5 DEG C (cooling extent is to drop 1 DEG C in every 15 minutes), 10 revs/min of mixing speed, stirring and crystallizing 8h；
(4) it filters, filter cake obtains 49.6g white solid, yield 99.3%, largest single impurity in 50 DEG C of vacuum drying 10h
0.02%, purity 99.99% (HPLC detection).
Embodiment 5: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 50ml dimethylformamide is added in reaction flask, is heated to molten
Solution, adds 200ml methyl tertiary butyl ether(MTBE), continues to be heated to 85 DEG C, stirs 30min；
(2) active carbon 1.5g is added, continues stirring 30 minutes, filters while hot；
(3) by 0 DEG C of methylene chloride 50ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly reduces, drop
After adding, continue to be cooled to -10 DEG C (cooling extent is to drop 1 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring and crystallizing
5h；
(4) it filters, filter cake obtains 49.7g white solid, yield 99.4%, largest single impurity in 45 DEG C of vacuum drying 8h
0.01%, purity 99.98% (HPLC detection).
Embodiment 6: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 75ml n-butanol is added in reaction flask, is heated until the temperature is raised to dissolve, then
225ml ether is added, continues to be heated to 85 DEG C, stirs 45min；
(2) active carbon 2.5g is added, continues stirring 30 minutes, filters while hot；
(3) it by 0 DEG C of n-hexane 300ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly reduces, is added dropwise
After, continue to be cooled to -8 DEG C (cooling extent is to drop 1 DEG C in every 10 minutes), 15 revs/min of mixing speed, stirring and crystallizing 9h；
(4) it filters, filter cake obtains 49.7g white solid, yield 99.5%, largest single impurity in 50 DEG C of vacuum drying 7h
0.02%, purity 99.99% (HPLC detection).
Embodiment 7: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g is added in reaction flask and ethyl acetate 25ml, heat temperature raising adds
25ml dimethylformamide continues to be heated to 85 DEG C, stirs 60min；
(2) active carbon 1.5g is added, continues stirring 30 minutes, filters while hot；
(3) by 0 DEG C of dichloromethane solution 25ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly drops
It is low, it is added dropwise, continues to be cooled to -5 DEG C (cooling extent is to drop 1 DEG C in every 15 minutes), 10 revs/min of mixing speed, stirring analysis
Brilliant 5h；
(4) it filters, filter cake obtains 46.9g white solid, yield 93.8%, largest single impurity in 40 DEG C of vacuum drying 5h
0.08%, purity 99.76% (HPLC detection).
Embodiment 8: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and n-hexane 150ml is added in reaction flask, is added after heat temperature raising
Dimethyl sulfoxide 50ml continues to be heated to 85 DEG C, stirs 40min；
(2) active carbon 2g is added, continues stirring 30 minutes, filters while hot；
(3) 3 DEG C of ether 100ml of above-mentioned filtrate agitation and dropping are dripped as the dropping temperature of cold solvent constantly reduces
Bi Hou continues to be cooled to -8 DEG C (cooling extent is to drop 2 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring and crystallizing 10h；
(4) it filters, filter cake obtains 47.8g white solid, yield 95.6%, largest single impurity in 45 DEG C of vacuum drying 8h
0.10%, purity 99.81% (HPLC detection).
Embodiment 9: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and 50ml dimethylformamide is added in reaction flask, after heat temperature raising again
Methylene chloride 50ml is added, continues to be heated to 85 DEG C, stirs 50min；
(2) active carbon 1.5g is added, continues stirring 30 minutes, filters while hot；
(3) by 0 DEG C of methyl tertiary butyl ether(MTBE) 200ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly drops
It is low, after being added dropwise, continue to be cooled to -10 DEG C (cooling extent is to drop 1 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring
Crystallization 5h；
(4) it filters, filter cake obtains 47.2g white solid, yield 94.4%, largest single impurity in 45 DEG C of vacuum drying 8h
0.09%, purity 98.82% (HPLC detection).
Embodiment 10: the preparation of citric acid tropsch imatinib crystal-form compound
(1) citric acid tropsch imatinib crude product 50g and petroleum ether 825ml is added in reaction flask, is added after heat temperature raising
N-butanol 150ml continues to be heated to 85 DEG C, stirs 50min；
(2) active carbon 2.5g is added, continues stirring 30 minutes, filters while hot；
(3) by 5 DEG C of methyl tertiary butyl ether(MTBE) 750ml of above-mentioned filtrate agitation and dropping, as the dropping temperature of cold solvent constantly drops
It is low, after being added dropwise, continue to be cooled to -10 DEG C (cooling extent is to drop 2 DEG C in every 15 minutes), 15 revs/min of mixing speed, stirring
Crystallization 12h；
(4) it filters, filter cake obtains 47.3g white solid, yield 94.6%, largest single impurity in 50 DEG C of vacuum drying 10h
0.11%, purity 98.72% (HPLC detection).
Embodiment 11: the preparation of citric acid tropsch imatinib crystal-form compound
Citric acid tropsch imatinib crude product 50g and n-butanol 150ml is added in reaction flask, to 85 DEG C after heat temperature raising, stirs
Mix 30min；Active carbon 2.5g is added, continues stirring 30 minutes, filters while hot；By 5 DEG C of petroleum ethers of above-mentioned filtrate agitation and dropping
750ml, as the dropping temperature of cold solvent constantly reduces, after being added dropwise, continuing to be cooled to -10 DEG C, (cooling extent is every 15
2 DEG C of minute drop), 15 revs/min of mixing speed, stirring and crystallizing 12h；It is white to obtain 45.1g in 50 DEG C of vacuum drying 8h for filtering, filter cake
Color solid, yield 90.1%, largest single impurity 0.12%, purity 98.33% (HPLC detection).
Embodiment 12: the preparation of citric acid tropsch imatinib crystal-form compound
Citric acid tropsch imatinib crude product 50g and dimethylformamide 100ml is added in reaction flask, to 85 after heat temperature raising
DEG C, stir 40min；Active carbon 2g is added, continues stirring 30 minutes, filters while hot；By 0 DEG C of dichloromethane of above-mentioned filtrate agitation and dropping
Alkane 200ml, as the dropping temperature of cold solvent constantly reduces, after being added dropwise, continuing to be cooled to -5 DEG C, (cooling extent is every 15
2 DEG C of minute drop), 15 revs/min of mixing speed, stirring and crystallizing 12h；It is white to obtain 45.1g in 50 DEG C of vacuum drying 8h for filtering, filter cake
Color solid, yield 90.9%, largest single impurity 0.12%, purity 98.41% (HPLC detection).
The X- that citric acid tropsch imatinib crystal-form compound obtained by embodiment 2~12 is obtained using Cu-K alpha ray measurement
Ray powder diffractogram is similar to Example 1.
Embodiment 13-22: the preparation of citric acid tropsch imatinib crystal-form compound
Operating procedure: being added citric acid tropsch imatinib crude product 50g and 25ml dimethylformamide in reaction flask, and heating rises
Temperature adds ethyl acetate 25ml to dissolving, and continues to be heated to 85 DEG C, stirs 30min；Active carbon 1.5g is added, continues to stir
It 30 minutes, filters while hot；By 0 DEG C of dichloromethane solution 25ml of above-mentioned filtrate agitation and dropping, with cold solvent dropping temperature not
It is disconnected to reduce, after being added dropwise, carry out program cooling, stirring and crystallizing；Filtering, filter cake obtain citric acid support in 40 DEG C of vacuum drying 8h
Method replaces Buddhist nun's white crystalline form powder.The X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurement and reality of obtained crystal
It is similar to apply example 1.
By carrying out embodiment 13-22, it can be deduced that the influence that stirring cooling Crystallization Process generates crystal form, experimental result
As shown in table 1 below.
1 citric acid tropsch imatinib of table prepares embodiment result
| Embodiment | Temperature-fall period | Rearing crystal time/h | Mixing speed | Yield/% | Largest single impurity/% | Purity/% |
| 13 | Program is cooled to -5 DEG C and drops 1 DEG C in every 15 minutes | 5 | 10 revs/min | 99.3 | 0.01 | 99.99 |
| 14 | Program is cooled to -10 DEG C and drops 2 DEG C in every 15 minutes | 8 | 15 revs/min | 99.2 | 0.01 | 99.99 |
| 15 | Program is cooled to -10 DEG C and drops 1 DEG C in every 15 minutes | 10 | 12 revs/min | 99.4 | 0.02 | 99.98 |
| 16 | Program is cooled to -5 DEG C and drops 2 DEG C in every 15 minutes | 12 | 13 revs/min | 99.0 | 0.02 | 99.99 |
| 17 | Program is cooled to -2 DEG C and drops 4 DEG C in every 15 minutes | 5 | 20 revs/min | 94.1 | 0.08 | 98.13 |
| 18 | Program is cooled to 0 DEG C and drops 5 DEG C in every 15 minutes | 8 | 5 revs/min | 93.4 | 0.10 | 97.94 |
| 19 | Program is cooled to -1 DEG C and drops 3 DEG C in every 10 minutes | 10 | 30 revs/min | 93.7 | 0.12 | 97.26 |
| 20 | Program is cooled to -3 DEG C and drops 4 DEG C in every 10 minutes | 12 | 25 revs/min | 90.1 | 0.12 | 98.11 |
| 21 | Program is cooled to -4 DEG C and drops 6 DEG C in every 10 minutes | 10 | 20 revs/min | 93.7 | 0.12 | 97.26 |
| 22 | Program is cooled to 0 DEG C and drops 3 DEG C in every 15 minutes | 12 | 10 revs/min | 90.1 | 0.12 | 98.11 |
The property of citric acid tropsch imatinib crystal form of the present invention is further illustrated below by test:
Reference substance 1 is citric acid tropsch imatinib crystal form prepared by CN 201410740110.1；
Reference substance 2 is citric acid tropsch imatinib crystal form prepared by CN 201610817563.9；
Reference substance 3 is citric acid tropsch imatinib crystal form prepared by CN 201710235123.7.
A citric acid tropsch imatinib novel crystal forms are tested compared with prior art physico-chemical property
Citric acid tropsch imatinib crystal form prepared by the present invention is compared with reference substance 1, reference substance 2 and reference substance 3, comparison
Situation is as shown in table 2.
The novel crystal forms of the present invention of table 2 are compared with the prior art result
As can be seen from Table 2, unlike the prior art, XRD characteristic peaks are different for crystal form of the present invention；Due to small particle
Active material has viscosity or poor mobility, and the active material of small particle is unsuitable for directly pressing in formulation test later
Piece measures citric acid tropsch imatinib novel crystal forms average grain diameter of the present invention between 82~90 μm by Particle Size Analyzer, is much larger than
Prior art crystal form, even particle size distribution, and this product angle of repose are less than prior art crystal form angle of repose, so that the stream of this product
Dynamic property is more preferable, is conducive to subsequent preparation, storage and transport, accounts for and have great advantage in pharmaceutical preparation；Compared to the prior art,
Novel crystal forms solubility of the invention significantly increases, and has positive effect to bioavilability in preparation research from now on.
Test two citric acid tropsch imatinib novel crystal forms stability tests
(1) influence factor stability test
According to 2015 Chinese Pharmacopoeia, 9001 material medicine and preparation stability test direction principle to 1-3 of the embodiment of the present invention
Citric acid tropsch imatinib crystal form, reference substance 1, reference substance 2 and the reference substance 3 of preparation carry out influence factor stability test.Temperature
It is placed under the conditions of 60 DEG C, relative humidity 90 ± 5% and intensity of illumination 4500Lx ± 500Lx 15 days and measures thermal stability, height respectively
Wet stability and light durability investigate the stability of citric acid tropsch imatinib crystal form provided by the invention, comparing result such as table 3
It is shown.
3 influence factor stability test result of table
As seen from Table 3, respectively under the conditions of temperature 60 C, relative humidity 90 ± 5% and intensity of illumination 4500Lx ± 500Lx
Place 15 days measurement thermal stability, high wet stability and light durability, citric acid tropsch imatinib crystal form largest single impurity of the present invention
All there is preferable stability with purity content, illustrate that the crystal form to temperature, water, illumination-insensitive, is convenient for long term storage, and it is right
Big according to product changes of contents, stability is bad.
(2) chronicity stability test
According to 2015 Chinese Pharmacopoeia, 9001 material medicine and preparation stability test direction principle to 1-3 of the embodiment of the present invention
Citric acid tropsch imatinib novel crystal forms, reference substance 1, reference substance 2 and the reference substance 3 of preparation carry out chronicity stability test, in temperature
It places 6 months under conditions of 25 ± 2 DEG C of degree, relative humidity 60 ± 5%, is surveyed respectively at 0,3,6,9,12,18,24 the end of month sampling
Qualitative shape, largest single impurity, total miscellaneous and purity, the results are shown in Table 4.
4 long-term stable experiment result of table (25 ± 2 DEG C of temperature, relative humidity 60 ± 5%)
As seen from Table 4, citric acid tropsch imatinib crystallization of the present invention is in 25 ± 2 DEG C of temperature, the condition of relative humidity 60 ± 5%
Significant change does not occur for color, form, purity in lower placement 24 months, and product stability is good.
Claims (10)
1. citric acid tropsch imatinib crystal-form compound shown in formula (I),
It is characterized by: its X-ray powder diffraction collection for being indicated with the 2 θ ± 0.2 ° angles of diffraction 3.71 °, 6.57 °,
10.88°、13.21°、15.09°、16.87°、20.01°、21.22°、25.47°、26.07°、27.69°、31.03°、32.02°、
Characteristic diffraction peak is shown at 33.18 ° and 36.74 °.
2. citric acid tropsch imatinib crystal-form compound as described in claim 1, which is characterized in that measured using Cu-K alpha ray
Obtained X-ray powder diffraction figure is as shown in Figure 1.
3. the preparation method of citric acid tropsch imatinib crystal form as claimed in claim 1 or 2, it is characterised in that including walking as follows
It is rapid:
(1) solvent A is poured into citric acid tropsch imatinib crude product, is heated until the temperature is raised to dissolve, solvent B is added later, is warming up to 85
DEG C stirring 30~60min；
(2) active carbon decoloring is added, continues to stir 30min, filter while hot；
(3) 0~5 DEG C of the solvent C that filtrate obtained above is continued to agitation and dropping pre-cooling, as the dropping temperature of solvent is continuous
It is reduced to out crystalline substance, program is cooled to -10 DEG C~-5 DEG C, precipitates crystal, and insulated and stirred is complete to crystallization；
(4) it filters, washing is dried in vacuo crystal, obtains the crystallization of citric acid tropsch imatinib.
4. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(1) in, the solvent A is dimethylformamide, n-butanol, dimethyl sulfoxide or acetonitrile.
5. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(1) in, the solvent B is ethyl acetate, methyl tertiary butyl ether(MTBE) or ether.
6. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(1) in, the mass volume ratio of citric acid tropsch imatinib crude product and solvent A is 1:0.5~3g/ml.
7. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(2) in, the quality of active carbon is the 3%~5% of citric acid tropsch imatinib crude product quality.
8. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(3) in, the solvent C is methylene chloride, petroleum ether or n-hexane；The volume ratio of solvent A, solvent B and solvent C be 1:1~
5:1~5.5.
9. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(3) in, program cooling dropped 1 DEG C~2 DEG C for every 15 minutes, was down to -10 DEG C~-5 DEG C, the crystallization time is 5~12h, mixing speed
It is 10~15 revs/min.
10. the preparation method of citric acid tropsch imatinib crystal-form compound according to claim 3, it is characterised in that: step
(4) in, vacuum drying refers to 5~10h of vacuum drying at 40~50 DEG C.
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