CN105130977A - Dasatinib compound and composition thereof - Google Patents
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- 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
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Abstract
A dasatinib compound. The X-ray powder diffraction spectrogram of the dasatinib compound shows characteristic peaks when 2[theta] value is 11.2 +/- 0.2 degrees, 14.2 +/- 0.2 degrees, 14.5 +/- 0.2 degrees, 17.0 +/- 0.2 degrees, 20.3 +/- 0.2 degrees, 22.8 +/- 0.2 degrees, 23.5 +/- 0.2 degrees, 25.0 +/- 0.2 degrees, 26.6 +/- 0.2 degrees and 27.0 +/- 0.2 degrees. The dasatinib crystal compound is increased in water solubility, is stable, is narrow in particle size distribution and is good in flowability. A dasatinib tablet prepared from the dasatinib crystal compound is increased in dissolution speed.
Description
Technical field
The present invention relates to a kind of Dasatinib compound, be specifically related to a kind of Dasatinib crystalline compounds and pharmaceutical composition thereof.
Background technology
Dasatinib (Dasatinib/Sprycel), for treating, comprise the adult patient of imatinib mesylate (Imatinibmesylate/Gleevec) resistance or all stadium of not tolerant chronic lymphocytic leukemia (chronic phase, acceleration period, lymphoid lineage cell acute transformation phase and myelocyte acute transformation phase).Meanwhile, FDA also treats the acute lymphoblastic leukemia adult patient to other therapy resistances or not tolerant Philadelphia Chromosome Positive through normal procedure approval Dasatinib.
Dasatinib belongs to many tyrosine kinase inhibitors, this time mainly according to from amounting to that 4 of comprising 911 routine patients are international, the security of multicenter II phase test and efficacy result and other supportive data and get permission for above-mentioned indication.The side reaction that it is the most often reported in clinical studies has fluid retention, gastrointestinal symptom and bleeding episode etc.; The serious side reaction the most often reported is heating, pleural effusion, heat generation neutral white) for granulocyte leukemia (CML).
FDA have approved the Sprycel (dasatinib) of Bristol Myers Squibb for adult patients, treat two kinds of new indications, to the insensitive each phase chronic myelocytic leukemia (CML) of the first-line drug chemotherapy such as imatinib, and to other therapies the acute lymphoblastic leukemia (ALL) of invalid or not tolerant Ph chromatin-positive.
In the medicine of approved listing, Sprycel is that the first can suppress the oral chemotherapeutic of multiple configuration tyrosine protein kinase Abl.At nanomolar concentration, this medicine can suppress Bcr-Abl, SRC kinase families (SRC, LCK, YES, FYN), c-KIT, EPHA2, and the multiple kinases such as PDGFR-B.By suppressing above-mentioned kinase whose effect, Sprycel can suppress the propagation of leukemia cell in CML and Ph+ALL marrow, but normoerythrocyte, white corpuscle and thrombocyte still can continue propagation.
The chemical name of Dasatinib 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, and its chemical structural formula is as follows:
Dasatinib formulation commercially available is at present based on oral tablet, patent application CN201110173055.9 discloses a kind of Dasatinib dispersible tablet, comprise Dasatinib or Dasatinib monohydrate ethyl high molecular polymer solid carrier, described solid carrier is one or more in polyvinylpyrrolidone, poloxamer, polyoxyethylene glycol, polyoxyethylene stearic acid ester.Patent application CN201010570259.1 discloses a kind of Dasatinib pharmaceutical composition altogether, containing active ingredient Dasatinib, pregelatinized Starch and tackiness agent, wherein each component is counted according to weight percent, Dasatinib 1-20%, pregelatinized Starch 20-35%, tackiness agent 60-79%.Patent application CN201110386631.8 discloses a kind of dasatinib tablet, the active ingredient Dasatinib of this tablet is anhydride, Dasatinib is ground into different-grain diameter scope, wherein D (0.1)=3.0-10 μm, D (0.5)=15-60 μm, D (0.9)=100-150 μm, also comprises weighting agent and tackiness agent, be prepared into Dasatinib tablet, the present invention controls the release of medicine by the granularity controlling active ingredient Dasatinib.
In order to improve the performance characteristic of Dasatinib, prior art improves the deficiency of its medicine itself in several ways.Such as, Chinese patent application CN201380031458.7 discloses Dasatinib polycomponent eutectic, be specially the combinations of substances such as Dasatinib and 4-HBA methyl esters, niacinamide, Progallin A, Tenox PG or menthol and form polycomponent crystallizing system, improve the water-soluble of Dasatinib in this way.Dasatinib polymorphic disclosed in Chinese patent application CN200910196987.8, Dasatinib polymorph is pharmaceutically acceptable, stable crystalline form.Chinese Patent Application No. CN201210554793.2 discloses the new crystalline form of Dasatinib monohydrate, for example number of patent application the 2013103447301.7th, CN201110215754.5 etc. disclose the crystalline form of Dasatinib, existing Dasatinib is by being prepared as solvate compounds or changing the solvability that crystalline form improves Dasatinib, but, other performance such as crystal grain distribution etc. need to improve, in order to widen other forms of Dasatinib to improve its solvability, for this reason, the invention provides a kind of new Dasatinib and composition.
Summary of the invention
The object of this invention is to provide a kind of Dasatinib crystalline compounds, the solvability of this compound is improved.
On the other hand, Dasatinib crystalline compounds provided by the invention, its narrow diameter distribution.
Again on the one hand, Dasatinib crystalline compounds provided by the invention, its good fluidity.
Another object of the present invention is to provide a kind of Dasatinib composition.
A kind of Dasatinib compound, its X-ray powder diffractogram as shown in Figure 1,
The chemical structure skeleton symbol of described Dasatinib is:
A kind of preparation method of above-mentioned Dasatinib compound, comprise the steps: Dasatinib to be dissolved in temperature be 40-60 DEG C dimethyl sulfoxide (DMSO), Virahol and acetonitrile mixed solvent in, after having dissolved, add ethyl acetate solvent, room temperature is reduced the temperature in 1-2 hour, keep 3 hours in room temperature, then, then be cooled to 0 ~-5 DEG C further, then, place 3-4 hour at 0 ~-5 DEG C, crystallize out, after washing, drying, obtain Dasatinib crystal.
In described solvent, the volume ratio of each component is: the volume ratio 10:(0.5-1 of dimethyl sulfoxide (DMSO), Virahol and acetonitrile): (1.5-2.0).
The volume of the ethyl acetate added and the volume ratio of mixed solvent are (1-1.5): 1.
A kind of Dasatinib composition, said composition comprises above-mentioned Dasatinib compound and pharmaceutical excipient.
Described Dasatinib composition is prepared into Dasatinib tablet.
Wherein, Dasatinib tablet comprises Dasatinib, weighting agent, tackiness agent, disintegrating agent and lubricant.
Below Dasatinib crystalline compounds of the present invention is described in detail:
The invention provides a kind of Dasatinib crystalline compounds, the X-ray powder diffractogram that this crystalline compounds uses the measurement of Cu-K alpha-ray to obtain, its X-ray powder diffractogram shows, it is 11.2 ° ± 0.2 ° at 2 θ, 14.2 ° ± 0.2 °, 14.5 ° ± 0.2 °, 17.0 ° ± 0.2 °, 20.3 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.5 ° ± 0.2 °, 25.0 ° ± 0.2 °, 26.6 ° ± 0.2 °, indicating characteristic peak, 27.0 ° ± 0.2 ° place.
The solvability of the preparation-obtained Dasatinib crystalline compounds of the present invention makes moderate progress.In the prior art in order to improve the water-soluble of Dasatinib or stability, be designed to multiple crystalline form or solvation material.Dasatinib crystal of the present invention not only solubility property improves, and narrow diameter distribution, good fluidity.The error of the active component content between each of tablet be prepared into is little.
Further, the preparation method of above-mentioned Dasatinib compound, comprise the steps: Dasatinib to be dissolved in temperature be 40-60 DEG C dimethyl sulfoxide (DMSO), Virahol and acetonitrile mixed solvent in, after dissolving completes, add ethyl acetate solvent, in 1-2 hour, reduce the temperature to room temperature, keep 3 hours in room temperature, then, be cooled to 0 ~-5 DEG C further again, then, place 3-4 hour at 0 ~-5 DEG C, crystallize out, obtains Dasatinib crystal after washing, drying.
In described solvent, the volume ratio of each component is: the volume ratio 10:(0.5-1 of dimethyl sulfoxide (DMSO), Virahol and acetonitrile): (1.5-2.0).
The volume of the ethyl acetate added and the volume ratio of mixed solvent are (1-1.5): 1.
While adding ethyl acetate solvent, stir with speed 250-350r/min.
In the solution dissolving Dasatinib, adding volume ratio is with it (1-1.5): the ethyl acetate solvent of 1, in adition process, ethyl acetate is disposable to add, in 1-2 hour, temperature is first dropped to room temperature, then insulation 3 hours, lower the temperature further more subsequently.After above-mentioned mixed solvent has dissolved Dasatinib, when adding ethyl acetate, by crystallization control process, the narrow diameter distribution of the crystal obtained, particle diameter accounts for more than 85% the number of particles of 130 ± 4.5 μm, and mobility is fine.
In the present invention, described room temperature refers to that temperature is 25 DEG C.
A kind of Dasatinib composition, containing above-mentioned Dasatinib crystalline compounds, said composition is prepared into Dasatinib tablet.
Wherein, Dasatinib tablet comprises Dasatinib, weighting agent, tackiness agent, disintegrating agent and lubricant.
The weight ratio of the described each component of Dasatinib tablet is:
Preferably,
The weight ratio of the described each component of Dasatinib tablet is:
Described weighting agent comprises the one in Xylitol, maltose alcohol, sorbyl alcohol, sucrose, gelatin, N.F,USP MANNITOL, starch paste, Mierocrystalline cellulose, Microcrystalline Cellulose, calcium phosphate, calcium sulfate, sodium-chlor etc., or its two or more mixture; Described tackiness agent comprises ethanolic soln, treated starch, polyvinylpyrrolidone, wherein preferably polyethylene pyrrolidone; Described disintegrating agent is the one in starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or its two or more mixing, its preferred low-substituted hydroxypropyl cellulose and/or croscarmellose sodium.
Described lubricant comprise silicon-dioxide, Magnesium Stearate, talcum powder, one or more mixing.
The preparation method of above-mentioned Dasatinib tablet comprises the steps:
(1) weighting agent of the recipe quantity of Dasatinib, disintegrating agent mixing are pulverized, obtain mixture A;
(2) binder solution is prepared;
(3) the mixture A of step (1) is mixed softwood processed with the tackiness agent that step (2) prepares, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds lubricant again, mixes, and measures drug content, compressing tablet.
The water-soluble raising of Dasatinib crystalline compounds provided by the invention, and more stable, narrow diameter distribution simultaneously, good fluidity.The Dasatinib tablet dissolution rate that this Dasatinib crystal preparation becomes is accelerated.
Accompanying drawing explanation
The X-ray powder diffractogram of Fig. 1 Dasatinib crystal
Fig. 2 Dasatinib tablet stripping curve
Embodiment
Be described in further detail to Dasatinib of the present invention and containing Dasatinib tablet below, do not limit protection scope of the present invention, its protection domain defines with claims.Detail disclosed in some provides complete understanding to each disclosed embodiment.But those skilled in the relevant art know, do not adopt these concrete details one or more, and adopt the situation of other material etc. can realize embodiment yet.
Embodiment 1
Dasatinib 10g is dissolved in temperature be 40 DEG C dimethyl sulfoxide (DMSO), Virahol and acetonitrile mixed solvent in 40mL, wherein, in mixed solvent, the volume ratio of dimethyl sulfoxide (DMSO), Virahol and acetonitrile is 10:1:1.5;
After dissolving completes, in the solution being dissolved with Dasatinib, add ethyl acetate solvent, the add-on of ethyl acetate is that liquor capacity is equal, stirs 5 minutes with speed 300r/min simultaneously, then stop stirring, in 2 hours, reduce the temperature to room temperature, keep 3 hours in room temperature, then be cooled to-5 DEG C further, finally, place 3 hours at-5 DEG C, crystallize out, obtain Dasatinib crystal with after anhydrous diethyl ether washing, drying.Gained Dasatinib crystal, through X-ray powder diffraction analysis, as shown in Figure 1, is 11.2 ° ° at 2 θ, 14.2 °, 14.5 °, 17.0 °, 20.3 °, 22.8 °, 23.5 °, 25.0 °, 26.6 °, indicating characteristic peak, 27.0 ° of places.
Ultimate analysis is carried out to Dasatinib, elemental analyser, detected result is carbon 54.11% (theoretical value 54.15%), protium 5.36% (theoretical value 5.33%), nitrogen element 20.09% (theoretical value 20.10%), element sulphur 6.61% (theoretical value 6.56%), chlorine element 7.25% (theoretical value 7.28%); Karl Fischer detects the moisture content <0.4% in Dasatinib crystal, not containing crystal water.
Embodiment 2
Dasatinib 10g is dissolved in temperature be 60 DEG C dimethyl sulfoxide (DMSO), Virahol and acetonitrile mixed solvent 50mL in, wherein, in mixed solvent, the volume ratio of dimethyl sulfoxide (DMSO), Virahol and acetonitrile is 10:0.5:1.5-;
After dissolving completes, in the solution being dissolved with Dasatinib, add ethyl acetate solvent, the add-on of ethyl acetate is liquor capacity 1.5 times, stir 5 minutes with speed 350r/min simultaneously, then stop stirring, in 2 hours, reduce the temperature to room temperature, keep 3 hours in room temperature, then, be cooled to 0 DEG C further again, finally, place 4 hours at 0 DEG C, crystallize out, obtains Dasatinib crystal after anhydrous diethyl ether washing, drying.Gained Dasatinib crystal is through X-ray powder diffraction analysis and Ka Shi moisture determination, and its result and embodiment 1 match.
Embodiment 3
Dasatinib 10g is dissolved in temperature be 50 DEG C dimethyl sulfoxide (DMSO), Virahol and acetonitrile mixed solvent 50mL in, wherein, in mixed solvent, the volume ratio of dimethyl sulfoxide (DMSO), Virahol and acetonitrile is 10:0.5:2.0;
After dissolving completes, in the solution being dissolved with Dasatinib, add ethyl acetate solvent, the add-on of ethyl acetate is that liquor capacity is equal, stir 2 minutes with speed 250r/min simultaneously, then stop stirring, in 2 hours, reduce the temperature to room temperature, keep 3 hours in room temperature, then, be cooled to-5 DEG C further again, finally, place 3 hours at-5 DEG C, crystallize out, obtains Dasatinib crystal after anhydrous diethyl ether washing, drying.Gained Dasatinib crystal is through X-ray powder diffraction analysis and Ka Shi moisture determination, and its result and embodiment 1 match.
Embodiment 4
The weight ratio of each component of Dasatinib tablet is:
The preparation method of Dasatinib tablet:
(1) sorbyl alcohol of the recipe quantity of Dasatinib, N.F,USP MANNITOL, croscarmellose sodium mixing are pulverized, obtain mixture A;
(2) take polyvinylpyrrolidone, make the aqueous povidone solution of 2% with water;
(3) the sticky mixed softwood processed of the tackiness agent mixture A of step (1) and step (2) prepared, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds Magnesium Stearate, mixes, and measures drug content, compressing tablet.
Embodiment 5
The weight ratio of each component of Dasatinib tablet is:
The preparation method of Dasatinib tablet:
(1) Xylitol of the recipe quantity of Dasatinib, Microcrystalline Cellulose, croscarmellose sodium mixing are pulverized, obtain mixture A;
(2) take ethanol, make the ethanolic soln of 70% with water, place for subsequent use;
(3) the sticky mixed softwood processed of the tackiness agent mixture A of step (1) and step (2) prepared, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds Magnesium Stearate, mixes, and measures drug content, compressing tablet.
Embodiment 6
The weight ratio of each component of Dasatinib tablet is:
The preparation method of Dasatinib tablet:
(1) Xylitol of the recipe quantity of Dasatinib, Microcrystalline Cellulose, cross-linked polyvinylpyrrolidone mixing are pulverized, obtain mixture A;
(2) take polyvinylpyrrolidone, make the aqueous povidone solution of 2% with water, place for subsequent use;
(3) the sticky mixed softwood processed of the tackiness agent mixture A of step (1) and step (2) prepared, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds silicon-dioxide, mixes, and measures drug content, compressing tablet.
Embodiment 7
The weight ratio of each component of Dasatinib tablet is:
The preparation method of Dasatinib tablet:
(1) maltose alcohol of the recipe quantity of Dasatinib, starch paste, cross-linked polyvinylpyrrolidone, croscarmellose sodium mixing are pulverized, obtain mixture A;
(2) take polyvinylpyrrolidone, make the aqueous povidone solution of 2% with water, place for subsequent use;
(3) the sticky mixed softwood processed of the tackiness agent mixture A of step (1) and step (2) prepared, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds silicon-dioxide, mixes, and measures drug content, compressing tablet.
Experimental example 1
This experimental example investigates the solvability of Dasatinib crystal prepared by the present invention, for the Dasatinib crystal that embodiment 1 ~ 3 is obtained.
The measuring method of solubleness is specially: carry out with reference to the measuring method under Chinese Pharmacopoeia version in 2010 two note on the use items.
The accurate Dasatinib crystal powder taking embodiment 1 ~ 3 obtained is appropriate respectively, add the water of a certain amount of 25 DEG C ± 2 DEG C, in room temperature be under the environment of 25 DEG C every 5 minutes powerful jolting 30 second, observe the dissolving situation in 30 minutes, during as cannot see particles of solute, be namely considered as dissolving completely.The results are shown in Table 1:
Table 1 Dasatinib crystal compares with the solubleness of Dasatinib in water
As can be seen from Table 1, the water-soluble of Dasatinib crystal that prepared by the present invention increases.
Experimental example 2
The mobility of this experimental example to the Dasatinib crystal of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the matters height on graph paper, Dasatinib crystal is freely flowed down from flare opening, until the cone top formed contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of Dasatinib accumulation horizon.
Table 2 Dasatinib crystal mobility is tested
| Batch | 1 | 2 | 3 | 4 | 5 | 6 | Mean value |
| θ(°) | 31 | 34 | 30 | 40 | 38 | 32 | 34.2 |
From the interpretation of table 2, the mobility of Dasatinib of the present invention is fine, and also carried out above-mentioned test to other Dasatinib crystal of embodiment 2,3, its result matches with it.
Experimental example 3
This experimental example tests the size distribution of Dasatinib crystalline compounds prepared by the embodiment of the present invention 1.Adopt laser scattering method.Be suspended in by Dasatinib crystalline compounds in the hexane of the Tween80 containing tensio-active agent 2%, stir suspensoid, ultrasonication makes Dasatinib disperse completely in 2 minutes, then detects the distribution of particle diameter with laser diffraction particle size distributed instruments.Its detected result:
The size distribution of table 3 Dasatinib crystal
From the interpretation of table 3, particle diameter is less than 5.56 μm of particles not to be had, and only occupy 0.25% at the particle of particle diameter 120.68 μm to 150.28 μm, namely particle diameter is mainly distributed between 25-120 μm.
Experimental example 4
This experimental example carries out contrast stability experiment to Dasatinib tablet (sample A) prepared by the present invention with the stability of the tablet (sample B) using commercially available Dasatinib (the honest pharmaceutcal corporation, Ltd that becomes a fine day in Jiangsu produces) to be prepared into.Except the difference that bulk drug uses, sample B adopts prescription and the preparation method of embodiment 4.Sample A, sample B measure dissolution rate according to " Chinese Pharmacopoeia " 2005 editions second annex XC first method respectively, solvent uses the hac buffer of PH4.5 as dissolution fluid, and the stripping quantity determination dissolution rate of Dasatinib is measured by efficient liquid phase chromatographic analysis, result is as shown in Figure 2.As can be seen from Figure 2, the stripping of Dasatinib tablet of the present invention is very fast, and cumulative concentration reaches more than 90% very soon, it can thus be appreciated that Dasatinib tablet In Vitro Dissolution of the present invention release is apparently higher than sample B.
To the experiment that the Dasatinib tablet of other embodiments of the present invention carries out as above, result matches with it.
Claims (8)
1. a Dasatinib compound, its X-ray powder diffractogram shows, and is 11.2 ° ± 0.2 ° at 2 θ, 14.2 ° ± 0.2 °, 14.5 ° ± 0.2 °, 17.0 ° ± 0.2 °, 20.3 ° ± 0.2 °, 22.8 ° ± 0.2 °, 23.5 ° ± 0.2 °, 25.0 ° ± 0.2 °, 26.6 ° ± 0.2 °, indicating characteristic peak, 27.0 ° ± 0.2 ° place.
2. the preparation method of a Dasatinib compound according to claim 1, comprise the steps: Dasatinib to be dissolved in dimethyl sulfoxide (DMSO), Virahol and acetonitrile that temperature is 40-60 DEG C, after having dissolved, add ethyl acetate solvent, room temperature is reduced the temperature in 1-2 hour, keep 3 hours in room temperature, then, then be cooled to 0 ~-5 DEG C further, then, place 3-4 hour at 0 ~-5 DEG C, crystallize out, is the Dasatinib after process.
3. a Dasatinib composition, said composition comprises Dasatinib compound according to claim 1 and pharmaceutical excipient.
4. Dasatinib composition according to claim 3, is characterized in that, described Dasatinib composition is prepared into Dasatinib tablet.
5. Dasatinib composition according to claim 4, is characterized in that, Dasatinib tablet comprises Dasatinib, weighting agent, tackiness agent, disintegrating agent and lubricant.
6. Dasatinib composition according to claim 4, it is characterized in that, the weight ratio of each component of described tablet is:
7. Dasatinib composition according to claim 4, it is characterized in that, described weighting agent comprises the one in Xylitol, maltose alcohol, sorbyl alcohol, sucrose, gelatin, N.F,USP MANNITOL, starch paste, Mierocrystalline cellulose, Microcrystalline Cellulose, calcium phosphate, calcium sulfate, sodium-chlor, or its two or more mixture; Described tackiness agent comprises ethanolic soln, treated starch, polyvinylpyrrolidone; Described disintegrating agent is the one in starch, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, or its two or more mixing.
8. preparation method according to claim 6, wherein the preparation method of Dasatinib tablet comprises the steps:
(1) weighting agent of the recipe quantity of Dasatinib, disintegrating agent mixing are pulverized, obtain mixture A;
(2) binder solution is prepared;
(3) the mixture A of step (1) is mixed softwood processed with the tackiness agent that step (2) prepares, granulate, dry, dry particle crosses the whole grain of 24 eye mesh screen;
(4) the dry particle after whole grain step (3) obtained adds lubricant again, mixes, and measures drug content, compressing tablet.
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