CN105130979A - Drug dasatinib compound for treatment of leukemia and preparation method thereof - Google Patents
Drug dasatinib compound for treatment of leukemia and preparation method thereof Download PDFInfo
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- CN105130979A CN105130979A CN201510484338.3A CN201510484338A CN105130979A CN 105130979 A CN105130979 A CN 105130979A CN 201510484338 A CN201510484338 A CN 201510484338A CN 105130979 A CN105130979 A CN 105130979A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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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
Belonging to the technical field of medicine, the invention relates to a drug dasatinib compound for treatment of leukemia and a preparation method thereof. An X-ray powder diffraction pattern obtained by Cu-K alpha ray measurement of the dasatinib compound is shown as Figure 1 in the specification. The dasatinib compound provided by the invention has good water solubility, is difficult to adsorb moisture, has low water and impurity content and good stability, and brings convenience for preparation of preparations.
Description
Technical field
The present invention relates to medical art, relate to one and treat leukemic medicine Dasatinib compound.
Background technology
Dasatinib, trade(brand)name SPRYCELTM, be a kind of oral tyrosine kinase inhibitor researched and developed by BMS company, for Adult chronic's myelogenous leukemia (CML), also can be used for the diseases such as the acute lymphoblastic leukemia for the treatment of Philadelphia Chromosome Positive.Its chemical name is N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] is amino]-5-thiazole carboxamides.
Because Dasatinib can have multiple different crystalline state, these different crystalline state are known as polymorphism, and the stability of compound can change along with the polymorphous change of often kind of polymorphism.So for same Dasatinib compound, its different crystalline form, polymorphic form are all different in stability, physical properties, solvability and preparation method.
For the polymorphic of medicine, different polymorphics can have different chemistry and physical property, comprises fusing point, chemical stability, apparent solubility, dissolution rate, optics and mechanical properties, vapour pressure and density.These character directly can affect process or the production of bulk drug and preparation, and can affect the stability of preparation, solubleness and bioavailability.Therefore, the polymorphic of medicine has great importance for the quality of pharmaceutical preparation, security and validity.
Because Dasatinib is poorly soluble, so its preparation bioavailability is lower, the uptake rate of medicine depends on dissolution rate again.In view of the pharmacy value of Dasatinib, although various crystal formation has been reported, but still in the urgent need to a kind of high specific surface area, the Dasatinib compound crystal being easy to suitability for industrialized production of stable in properties.Because obtain purity excellent, have and determine crystalline form very much and the fabulous compound of circulation ratio is important, in preparation, consequently present the valuable characteristic of tool, and enough stable to make it can long-time storage and not to the particular requirement of temperature, light, humidity or oxygen level.
The present inventor starts with from the research of Dasatinib solid chemical material existence, a kind of Dasatinib crystalline compounds has been prepared through a large amount of tests, surprisingly find through overtesting, this compound crystal good water solubility, not easily moisture absorption, moisture and the low and good stability of foreign matter content, the preparation for preparation brings conveniently.
Summary of the invention
Primary goal of the invention of the present invention is to propose a kind of Dasatinib compound.
Second goal of the invention of the present invention is the preparation method proposing Dasatinib compound.
In order to realize the first object of the present invention, the technical solution used in the present invention is:
One treats leukemic medicine Dasatinib compound, and described Dasatinib compound is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.
Polymorph in pharmaceuticals phenomenon is ubiquitous problem in present drug research.The polymorphism of medicine can affect its physico-chemical property, and then may have influence on the clinical efficacy of medicine.Dasatinib of the prior art is poorly soluble, so its preparation bioavailability is lower.The present inventor obtains a kind of good water solubility by a large amount of tests, not easily moisture absorption, moisture and the low and good stability of foreign matter content, the Dasatinib compound that the preparation for preparation brings convenience.
In order to realize the second object of the present invention, the technical solution used in the present invention is:
A preparation method for Dasatinib compound, the method comprises the steps:
Dasatinib is dissolved in the mixed solvent of methyl-sulphoxide, 2-picoline; First add the mixed solvent A of acetone, tetracol phenixin and sherwood oil with the speed of 35-40ml/min, limit edged stirs, control temperature 45-50 DEG C, growing the grain 2-3 hour; And then the mixed solvent B of acetone and ethanol is added with the speed of 45-50ml/min, after growing the grain 1-2 hour, cooling, then keeps stirring velocity 50-60 rev/min of stirring and crystallizing, growing the grain 2-3 hour; Filter, drying obtains Dasatinib crystalline compounds.
As preferably, the volume of the mixed solvent of described methyl-sulphoxide, 2-picoline be the 6-7 of Dasatinib weight doubly, the volume ratio of methyl-sulphoxide and 2-picoline is 5:3.5, and temperature is 45-50 DEG C.
As preferably, described elder generation adds 8-9 that the volume total amount of the mixed solvent A of acetone, tetracol phenixin and sherwood oil is Dasatinib weight doubly with the speed of 35-40ml/min, the volume ratio of acetone, tetracol phenixin and sherwood oil is 4:2:1.
As preferably, doubly, the volume ratio of acetone and ethanol is 1:1 to the 5-7 that the described volume total amount adding the mixed solvent B of acetone and ethanol again with the speed of 45-50ml/min is Dasatinib weight.
As preferably, described cooling is be cooled to-5-0 DEG C with the speed of 15-20 DEG C/h.
As preferably, described drying is 45-50 DEG C, drying under reduced pressure.
The present inventor is after having carried out large quantifier elimination to it, obtain above-mentioned preparation method, prepare a kind of Dasatinib crystalline compounds being different from prior art, surprisingly find through overtesting, this compound crystal good water solubility, not easily moisture absorption, moisture and the low and good stability of foreign matter content, the preparation for preparation brings conveniently.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction pattern that the Dasatinib compound of embodiment 1 preparation uses the measurement of Cu-K alpha-ray to obtain.
Embodiment
The specific embodiment of the present invention is only limitted to explain further and the present invention is described, does not limit Composition of contents of the present invention.
embodiment 1:the preparation of Dasatinib compound
Be dissolved in by Dasatinib in the mixed solvent of methyl-sulphoxide that 45 DEG C of volumes are 6 times of Dasatinib weight, 2-picoline, the volume ratio of methyl-sulphoxide and 2-picoline is 5:3.5; First add the acetone of 8 times that volume total amount is Dasatinib weight, the mixed solvent A of tetracol phenixin and sherwood oil with the speed of 35ml/min, the volume ratio of acetone, tetracol phenixin and sherwood oil is 4:2:1, the stirring of limit edged, control temperature 45 DEG C, growing the grain 2 hours; And then add the acetone of 5 times that volume total amount is Dasatinib weight and the mixed solvent B of ethanol with the speed of 45ml/min, the volume ratio of acetone and ethanol is 1:1, growing the grain is after 1 hour, be cooled to-5 DEG C with the speed of 15 DEG C/h, then keep stirring velocity 50 revs/min of stirring and crystallizing, growing the grain 2 hours; Filter, 45 DEG C, drying under reduced pressure obtains Dasatinib crystalline compounds.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Dasatinib compound as shown in Figure 1.
embodiment 2:the preparation of Dasatinib compound
Be dissolved in by Dasatinib in the mixed solvent of methyl-sulphoxide that 47.5 DEG C of volumes are 6.5 times of Dasatinib weight, 2-picoline, the volume ratio of methyl-sulphoxide and 2-picoline is 5:3.5; First add the acetone of 8.5 times that volume total amount is Dasatinib weight, the mixed solvent A of tetracol phenixin and sherwood oil with the speed of 37.5ml/min, the volume ratio of acetone, tetracol phenixin and sherwood oil is 4:2:1, limit edged stirs, control temperature 47.5 DEG C, growing the grain 2.5 hours; And then add the acetone of 6 times that volume total amount is Dasatinib weight and the mixed solvent B of ethanol with the speed of 47.5ml/min, the volume ratio of acetone and ethanol is 1:1, growing the grain is after 1.5 hours, be cooled to-2.5 DEG C with the speed of 17.5 DEG C/h, then keep stirring velocity 55 revs/min of stirring and crystallizing, growing the grain 2.5 hours; Filter, 47.5 DEG C, drying under reduced pressure obtains Dasatinib crystalline compounds.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Dasatinib compound is similar to embodiment 1.
embodiment 3:the preparation of Dasatinib compound
Be dissolved in by Dasatinib in the mixed solvent of methyl-sulphoxide that 50 DEG C of volumes are 7 times of Dasatinib weight, 2-picoline, the volume ratio of methyl-sulphoxide and 2-picoline is 5:3.5; First add the acetone of 9 times that volume total amount is Dasatinib weight, the mixed solvent A of tetracol phenixin and sherwood oil with the speed of 40ml/min, the volume ratio of acetone, tetracol phenixin and sherwood oil is 4:2:1, the stirring of limit edged, control temperature 50 DEG C, growing the grain 3 hours; And then add the acetone of 7 times that volume total amount is Dasatinib weight and the mixed solvent B of ethanol with the speed of 50ml/min, the volume ratio of acetone and ethanol is 1:1, growing the grain is after 2 hours, be cooled to 0 DEG C with the speed of 20 DEG C/h, then keep stirring velocity 60 revs/min of stirring and crystallizing, growing the grain 3 hours; Filter, 50 DEG C, drying under reduced pressure obtains Dasatinib crystalline compounds.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to prepared Dasatinib compound is similar to embodiment 1.
test example 1:wettability test
This test example compares the water absorbability of the Dasatinib of Dasatinib compound provided by the invention and prior art.
Test method: respectively under the condition of humidity 60% and 90%, room temperature, each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 1.
Table 1, sample water absorbability measurement result
Wherein:
Sample 1: the Dasatinib that the embodiment of the present invention 1 is obtained;
Sample 2: the Dasatinib that the embodiment of the present invention 2 is obtained;
Sample 3: the Dasatinib that the embodiment of the present invention 3 obtains;
Sample 4, Dasatinib bulk drug product (Lianyungang Ruizhong Pharmaceutical Co., Ltd.).
As can be seen from above-mentioned test-results, compared with the Dasatinib of prior art, the water absorbability that Dasatinib tool provided by the present invention has clear improvement.
Also carried out above-mentioned test to the Dasatinib compound prepared by other embodiment of the present invention, its result obtained is similar.
test example 2:dissolubility test
Test with reference to Chinese Pharmacopoeia, method is: it is appropriate that precision takes Dasatinib, and slowly add the water of 25 DEG C, the powerful jolting 30 seconds every 5 minutes, observes the dissolving situation in 30 minutes, the results are shown in Table 2.
Table 2 dissolubility test result
As seen from the experiment, the solvability of Dasatinib crystalline compounds of the present invention in water improves close to 17.7 times than contrast medicine.
Carried out similar test to other embodiments, acquired results is similar to embodiment 1.
test example 3:stability test
l, exposure experiments to light
Evenly share in uncovered culture dish by Dasatinib embodiment 1 crystal-form compound of the present invention, thickness≤5mm, adjustable range, make intensity of illumination be 4500 ± 500Lx, respectively at 5, sampling in 10 days detects, and contrasts with the result of 0 day, the results are shown in Table 3.
Table 3 exposure experiments to light (4500 ± 5001x)
2, high temperature test
Dasatinib embodiment 1 crystal-form compound of the present invention be positioned in sealing clean vial, be placed in 60 DEG C of thermostatic drying chambers, respectively at 5, sampling in 10 days detects, and contrasts with the result of 0 day, the results are shown in Table 4.
Table 4 high temperature test (60 DEG C)
3, high wet test
The embodiment of the present invention 1 Dasatinib crystal-form compound is evenly shared in uncovered culture dish, thickness≤5mm, be placed in room temperature (about 25 DEG C), relative humidity is in the fixed temperature and humidity incubator of 75 ± 5%, respectively at 5, sampling in 10 days measures, and contrasts with the result of 0 day.The results are shown in Table 5.
The high wet test of table 5 (room temperature, relative humidity 75 ± 5%)
4, accelerated test
Packed by the embodiment of the present invention 1 Dasatinib crystal-form compound polyethylene film plastic bag sealing, be placed in 40 ± 2 DEG C, relative humidity is in the fixed temperature and humidity incubator of 75 ± 5%, place six months, respectively at 1,2,3,6 samplings at the end of month detect, and contrast with the result of 0 month.The results are shown in Table 6.
Table 6 accelerated test (40 DEG C, relative humidity 75% ± 5%)
Above experimental result shows, the Dasatinib crystal-form compound that the present invention obtains related substance under illumination condition has a small amount of increase, and moisture content is substantially unchanged; In high temperature test (60 DEG C), outward appearance is without obvious change, and moisture content is substantially unchanged, and related substance has a small amount of increase; Dasatinib crystal-form compound of the present invention its outward appearance and related substance in high wet test all do not have considerable change, and moisture content slightly changes; Acceleration study result shows that its physico-chemical property of Dasatinib bulk drug with crystal formation of the present invention is relatively stable.Can also learn crystal-form compound of the present invention not only good stability by above result, and moisture, foreign matter content are all lower.
This product, in long-term reserved sample observing test, is not observed crystal formation and is changed; Related substance has the increase of small amount.Test shows that the crystal habit of this crystal formation is stablized, suitable long-term preservation.
Carried out similar test to other embodiments, acquired results is similar to embodiment 1.
Claims (7)
1. treat a leukemic medicine Dasatinib compound, it is characterized in that: described Dasatinib compound is crystal, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.
2. prepare a method for treatment according to claim 1 leukemic medicine Dasatinib compound, it is characterized in that comprising the following steps: Dasatinib is dissolved in the mixed solvent of methyl-sulphoxide, 2-picoline; First add the mixed solvent A of acetone, tetracol phenixin and sherwood oil with the speed of 35-40ml/min, limit edged stirs, control temperature 45-50 DEG C, growing the grain 2-3 hour; And then the mixed solvent B of acetone and ethanol is added with the speed of 45-50ml/min, after growing the grain 1-2 hour, cooling, then keeps stirring velocity 50-60 rev/min of stirring and crystallizing, growing the grain 2-3 hour; Filter, drying obtains Dasatinib crystalline compounds.
3. the preparation method for the treatment of according to claim 2 leukemic medicine Dasatinib compound, it is characterized in that: the volume of the mixed solvent of described methyl-sulphoxide, 2-picoline is 6-7 times of Dasatinib weight, the volume ratio of methyl-sulphoxide and 2-picoline is 5:3.5, and temperature is 45-50 DEG C.
4. the preparation method for the treatment of according to claim 2 leukemic medicine Dasatinib compound, it is characterized in that: described elder generation adds 8-9 that the volume total amount of the mixed solvent A of acetone, tetracol phenixin and sherwood oil is Dasatinib weight doubly with the speed of 35-40ml/min, the volume ratio of acetone, tetracol phenixin and sherwood oil is 4:2:1.
5. the preparation method for the treatment of according to claim 2 leukemic medicine Dasatinib compound, it is characterized in that: doubly, the volume ratio of acetone and ethanol is 1:1 to the 5-7 that the described volume total amount adding the mixed solvent B of acetone and ethanol again with the speed of 45-50ml/min is Dasatinib weight.
6. the preparation method for the treatment of according to claim 2 leukemic medicine Dasatinib compound, is characterized in that: described cooling is be cooled to-5-0 DEG C with the speed of 15-20 DEG C/h.
7. the preparation method for the treatment of according to claim 2 leukemic medicine Dasatinib compound, is characterized in that: described drying is 45-50 DEG C, drying under reduced pressure.
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Cited By (1)
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| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
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Application publication date: 20151209 |