CN103059013A - New crystal of Dasatinib monohydrate and preparation method thereof - Google Patents
New crystal of Dasatinib monohydrate and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicines, in particular to a crystal III of Dasatinib monohydrate, its preparation method and pharmaceutical composition. The crystal III of Dasatinib monohydrate provided in the invention is very stable under the conditions of illumination, high temperature, high humidity and accelerated testing. The pharmaceutical composition of crystal III of Dasatinib monohydrate has good dissolubility, and can be stable under high temperature conditions. In addition, compared with prior art, the preparation method provided in the invention has the advantages of simple operation and controllable quality.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to Form II I, preparation method and the pharmaceutical composition thereof of Dasatinib monohydrate.
Background technology
The Dasatinib monohydrate, molecular formula C
22H
26ClN
7O
2S.H2O, molecular weight 506.02, CAS863127-77-9.Commodity are called SPRYCEL, are by a kind of oral TYR kinase inhibitor of BMS company research and development, are used to into human chronic myeloblastic leukemia (CML), also can be used for treating the diseases such as acute lymphoblastic leukemia of Philadelphia chromatin-positive.Its chemical name is N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidyl] amino]-the 5-thiazole carboxamides, chemical structure is as follows:
Put down in writing a kind of crystalline form of Dasatinib monohydrate in Chinese patent CN200580011916.6 (hereinafter referred " the 916 ") file, and the crystalline form of two kinds of solvates, and disclosed the preparation method of corresponding crystalline form.Wherein the preparation method of crystalline state monohydrate adds 22 times of ethanol and 3 times of water to the Dasatinib anhydride, be heated to 75 ℃ of dissolvings (or filtration), and 75-80 ℃ of lower the maintenance with fully dissolving of acquisition, and then add the water of 8 times of amounts, and guarantee that the speed that water adds remains between 75-80 ℃, be chilled to 75 ℃, add the crystal seed of monohydrate, be chilled to 70 ℃ and kept about 1 hour at 70 ℃.In 2 hours, be chilled to 5 ℃ from 70 ℃, and 0-5 ℃ of maintenance at least 2 hours, filter, washing, drying under reduced pressure obtains.From actually operating, the Dasatinib anhydride is difficult to dissolving in the ethanolic soln of patent consumption, even also can't realize dissolving fully under reflux state, and need to add in advance crystal seed and just can obtain required crystalline form.Cooling process is complicated, and restive, energy consumption is also larger.
Put down in writing the crystalline form I of Dasatinib monohydrate and the polymorph II of Dasatinib in CN201019026056.3 (hereinafter referred " the 056 ") file, and disclosed the preparation method of corresponding crystalline form.Wherein the crystalline form I of Dasatinib monohydrate is that the Dasatinib anhydride is added in dimethyl formamide or the dimethyl sulfoxide (DMSO), heating for dissolving, then drip the mixed solvent system of a kind of water and organic solvent, wherein organic solvent is insoluble or sl. sol. one or more the mixed solvent of Dasatinib, after the insulation, stir lower slow cooling to 0-5 ℃, solid is separated out fully and growing the grain, filter, drying obtains the Dasatinib monohydrate of crystalline form I.Obviously, the crystal mass that obtains under this complex system is restive, and will bring during suitability for industrialized production and be difficult in a large number the organic liquid waste processed, brings immense pressure to environment protection.
For molecular structure is identical but the medicine that crystalline form is different, it might have different bioavailabilities, solubleness, dissolution rate, chemical physical stability and flowability.These character can directly affect processing or the production of bulk drug and preparation.For example: needle crystal is because being with a lot of static, thereby seems very sticking.Therefore the polymorphic of medicine has great importance for quality, security and the validity of pharmaceutical preparation.
In view of the pharmacy value of Dasatinib monohydrate, although the crystalline form of Dasatinib monohydrate have been reported, but still excellent in the urgent need to a kind of physicochemical property, the Dasatinib monohydrate crystal that is easy to suitability for industrialized production of stable in properties.Because obtain purity good, have very definite crystalline form and this fabulous compound of circulation ratio is important, consequently aspect preparation, present the valuable characteristic of tool, and enough stable so that it can store for a long time not to the particular requirement of temperature, light, humidity or oxygen level.
Summary of the invention
The present inventor is through a large amount of research, be surprised to find the new crystalline form of Dasatinib monohydrate, success overcome various defectives in the present production, it is excellent to have obtained physicochemical property, the Dasatinib monohydrate crystal that is easy to suitability for industrialized production of stable in properties is referred to as the Form II I of Dasatinib monohydrate.Described crystalline form is especially being showed valuable characteristic aspect the preparation.
Purpose of the present invention provides a kind of novel polymorphic thing of Dasatinib monohydrate, i.e. the new Form II I of Dasatinib monohydrate.
Specifically the invention provides a kind of Form II I of Dasatinib monohydrate, its X-ray powder diffraction is consistent with shown in Fig. 1 basically, and there is diffraction peak at the 2 θ angles that show with kilsyth basalt at 4.5 ± 0.2,9.1 ± 0.2,11.1 ± 0.2,13.7 ± 0.2,15.1 ± 0.2,17.8 ± 0.2,19.5 ± 0.2,23.1 ± 0.2,25.8 ± 0.2,27.9 ± 0.2 places.
Compare with the monohydrate of the Dasatinib of putting down in writing in " 916 " file, the Form II I of Dasatinib monohydrate has better physico-chemical property, and stability is better, and faster stripping is arranged.
Another object of the present invention provides the preparation method of the new Form II I of Dasatinib monohydrate, includes but not limited to following:
(1) Dasatinib is added in an amount of solvent; Solvent comprises methyl alcohol, acetonitrile, n-propyl alcohol, Virahol, acetone, dioxane, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), dimethyl formamide etc. can dissolve Dasatinib and can dissolve each other with water under heating condition solvent.Dasatinib is different with the different solubility of solvent from weight and the volume ratio of solvent, so that Dasatinib is dissolved as target fully.
(2) heating makes its dissolving; Heating temperature can be from room temperature to solvent refluxing, preferably under refluxad dissolving, and the quantity of solvent of using like this is minimum.
(3) add while hot suitable quantity of water; The consumption of water is different with the difference of solvent species, and the amount of adding muddiness just occurred take solution and become clearly as standard immediately again.
(4) leave standstill lower slow cooling and separate out the part crystal by the Dasatinib monohydrate, cooling rate is no faster than 30 ℃/hour; Preferred cooling rate is no faster than 20 ℃/hour, and more preferably cooling rate is not higher than 10 ℃/hour.
(5) add remaining water to solution for continuous, crystallization filters, and drying namely gets the Dasatinib monohydrate of crystal form II I.The product yield that obtains like this is higher, and can enhance productivity.
Although a kind of crystalline form of the known Dasatinib monohydrate of prior art " 916 " file can be with optionally making by the operation of complexity with water mixed solvent by ethanol or other alcohol, surprisingly can dissolve Dasatinib with methyl alcohol or other heating and the mixture of the solvent that dissolves each other with water and water can selectivity obtains the crystallization of different crystal forms by suitable processing.
With compare " 916 " file in the crystalline form of the Dasatinib monohydrate put down in writing compare, the crystal purity that the present invention obtains is higher, homogeneous more operates easylier, process repeatability is better, is more suitable for preparation and uses.
Compare with the crystalline form I of having put down in writing the Dasatinib monohydrate in " 056 " file, complicated solvent system is used in the preparation of the crystalline form I of Dasatinib monohydrate, and the purity of restive crystal also is unfavorable for the removal of environment protection and residual solvent.And single solvent and water are only used in the preparation of the Form II I of Dasatinib monohydrate, are more suitable for the recycling of solvent, have reduced the pollution to environment, are conducive to the reduction of industrial production cost.
The 3rd purpose of the present invention provides the medicine that reaches the Form II I that contains above-mentioned Dasatinib monohydrate and the composition of pharmaceutical excipient.The Dasatinib monohydrate 1～500mg that contains Form II I in this pharmaceutical composition preferably, contains the about 20mg of Dasatinib, 50mg, 70mg, 100mg crystalline form thing III.Crystalline form thing III of the present invention can add suitable pharmaceutical excipient, makes various formulations, to satisfy all kinds of patients' needs.
The application of the Form II I of described Dasatinib monohydrate in preparation treatment cancer drug.
X-powdery diffractometry testing tool involved in the present invention is D8 advence diffractometer (German Brooker company limited); Copper target, graphite monochromator, tube voltage 40Kv, tube current 40mA, sweep velocity 0.2S/ step
Related substance testing conditions and method involved in the present invention are: according to high effective liquid chromatography for measuring (2005 editions two appendix of Chinese Pharmacopoeia)
Condition determination: be weighting agent with octadecylsilane chemically bonded silica; Water A is the 0.01mol/L SODIUM PHOSPHATE, MONOBASIC, 0.1% triethylamine, and phosphoric acid adjust pH to 3.0, organic phase B are acetonitrile, flow velocity 1.0ml/min; The detection wavelength is 220nm; According to the form below carries out gradient elution, and number of theoretical plate calculates by the Dasatinib peak and is not less than 2000; The resolution of Dasatinib and adjacent impurity peaks should meet the requirements.
Content assaying method: get this product, accurately weighed, add ultrasonic the making of moving phase and dissolve and dilute and make the solution that contains approximately 50 μ g among every 1ml, precision is measured 20 μ l, injection liquid chromatography, record color atlas.It is an amount of that other gets the Dasatinib reference substance, accurately weighed, adds to flow mutual-assistance dissolving and make the solution that contains approximately 50 μ g among every 1ml, measures with method.Press external standard method with calculated by peak area, and get final product.
Dissolution determination method sample thief involved in the present invention, according to dissolution method (2005 editions two appendix XC the second methods of Chinese Pharmacopoeia), take the pH4.0 acetate buffer solution as dissolution medium, rotating speed is that per minute 60 turns, in accordance with the law operation is got a little when 10min, 15min, 30min, 45min, 60min respectively and is carried out ultraviolet detection (λ=320).
The Dasatinib monohydrate stable crystal formation experiment of crystalline form thing III
1, illumination experiment
Operation: get this product and be tiled in right amount (about 2mm thickness) in the culture dish, place under the 4500Lx scholar 500Lx strong illumination condition and placed 10 days, detect in sampling in the 5th day, 10 days,
2, high temperature experiment
Get this product and be tiled in right amount (about 2mm thickness) in the culture dish, place 60 ℃ thermostat container to place 10 days, detect in sampling in the 5th, 10 day
3, high humidity experiment
Get this product and be tiled in right amount (about 2mm thickness) in the culture dish, place under 2 ℃ of 25 ℃ of scholars of room temperature, relative humidity RH90% scholar's 5% the condition and placed 10 days, detect in sampling in the 5th, 10 day
4, accelerate experiment
This product is pressed commercially available back, puts under 40 ℃ ± 2 ℃ of temperature, relative humidity RH75% ± 5% condition, placed 6 months, in sampling at the 1st, 2,3,6 the end of month once,
By above-mentioned experimental data as can be known, Dasatinib hydrate novel Form II I of the present invention is very stable under illumination, high temperature, high humidity and acceleration experiment condition.
The preparation high temperature experiment of the Dasatinib monohydrate of crystalline form thing III
Experimental technique:
The crystalline form of above-mentioned different schemes is prepared into solid preparation according to same formulation method (supplementary product kind, consumption identical), places 60 ℃ thermostat container to place 10 days, in the 0th, 5,10 day sampling and measuring, with 0 day relatively.Measurement result sees the following form.
The high temperature experimental result
Experiment conclusion: above-mentioned experiment shows that the new Form II I of Dasatinib monohydrate of the present invention can prepare the more outstanding product of quality (dissolution rate is better, and product is more stable).
Description of drawings:
The XRPD figure of Fig. 1 Dasatinib monohydrate of the present invention Form II I
10 days XRPD of Fig. 2 Dasatinib monohydrate of the present invention Form II I strong illumination figure;
10 days XRPD of Fig. 3 Dasatinib monohydrate of the present invention Form II I high temperature figure;
10 days XRPD of the high humidity figure of Fig. 4 Dasatinib monohydrate of the present invention Form II I;
Fig. 5 Dasatinib monohydrate of the present invention Form II I tablet formulation and patent " 916 " tablet formulation stripping curve comparison diagram.
Embodiment
The following example is used for explanation the present invention, but should not be construed to limitation of the present invention.
Embodiment 1:
The preparation of Dasatinib monohydrate Form II I
Get in the methyl alcohol of 28g Dasatinib adding 2000ml, be heated to dissolving under stirring, filtered while hot one time stirs the lower 1400ml of adding water in the filtrate, stop to stir, fine crystals is slowly separated out in cooling naturally, add again 600ml water after 3 hours under the stirring at room, add and stop to stir, place crystallization.The white crystal that suction filtration is separated out, a small amount of methanol wash, 60 ℃ of lower vacuum-dryings, Vanadium Pentoxide in FLAKES helps dried, obtains product 23g, white crystalline powder.
Embodiment 2:
The preparation of Dasatinib monohydrate Form II I
Get in the acetone of 10g Dasatinib adding 1000ml, being heated to the dissolving that refluxes under stirring, filtered while hot one time adds 500ml water under stirring in the filtrate, stop to stir, fine crystals is slowly separated out in cooling naturally, add again 500ml water after 4 hours under the stirring at room, add and stop to stir, place crystallization.The white crystal that suction filtration is separated out, a small amount of washing, 60 ℃ of lower vacuum-dryings, Vanadium Pentoxide in FLAKES helps dried, obtains product 8.4g, white crystalline powder.
Embodiment 3:
The preparation of Dasatinib monohydrate Form II I
Get in the dimethyl formamide of 10g Dasatinib adding 50ml, be heated to 70 ℃ of dissolvings under stirring, filtered while hot one time stirs the lower 75ml of adding water in the filtrate, stop to stir, naturally cooling is to slowly separating out fine crystals, add again 30ml water under the stirring at room, add and stop to stir, place crystallization.The white crystal that suction filtration is separated out, a small amount of washing, 60 ℃ of lower vacuum-dryings, Vanadium Pentoxide in FLAKES helps dried, obtains product 7.3g, white crystalline powder.
Embodiment 4:
The preparation of Dasatinib monohydrate Form II I
Get in the acetonitrile of 5g Dasatinib adding 300ml, being heated to the dissolving that refluxes under stirring, filtered while hot one time adds 100ml water under stirring in the filtrate, stop to stir, naturally cooling is to slowly separating out fine crystals, add again 50ml water under the stirring at room, add and stop to stir, place crystallization.The white crystal that suction filtration is separated out, a small amount of washing, 60 ℃ of lower vacuum-dryings, Vanadium Pentoxide in FLAKES helps dried, obtains product 2.8g, white crystalline powder.
Embodiment 5
The prescription of Dasatinib tablet, preparation technology and stripping comparative experiments
Carry out respectively preparation preparation and stripping experiment with Dasatinib monohydrate Form II I of the present invention and according to the crystalline form of " 916 " file record preparation.
Sheet heart prescription:
| The Dasatinib monohydrate | 0.518g |
| Lactose | 0.67g |
| Microcrystalline Cellulose | 0.67g |
| Hypromellose | 0.11g |
| Croscarmellose sodium | 0.04 |
| 30% ethanol | In right amount |
| Magnesium Stearate | 0.01g |
| Make altogether | 100 |
The preparation method: Dasatinib was pulverized 200 mesh sieves; The main ingredient of recipe quantity mixes with the equivalent method of progressively increasing with the croscarmellose sodium of lactose, Microcrystalline Cellulose, hydroxy propyl cellulose and 1/2 recipe quantity, crosses 80 mesh sieves and namely gets mixed powder 3 times.Be wetting agent softwood processed with 30% ethanol, 24 mesh sieves are granulated, 60 ℃ of dryings, and the whole grain of 24 mesh sieves adds recipe quantity Magnesium Stearate and residue croscarmellose sodium, mixes.Heavy and the pressure of adjustment sheet, compressing tablet.
Carry out respectively preparation preparation and stripping experiment with Dasatinib monohydrate Form II I of the present invention and according to the crystalline form of " 916 " file record preparation, the result is as follows.
The dissolution rate comparative experiments
According to aforementioned dissolution determination method, carry out dissolution determination, dissolution data and the document crystal formation dissolution data of Dasatinib monohydrate Form II I are determined as follows respectively:
Table 1: the dissolution rate of Dasatinib monohydrate Form II I
Table 2: the dissolution rate of Dasatinib monohydrate " 916 " crystalline form
Tablet of the present invention and patent " 916 " tablet formulation stripping curve is relatively seen accompanying drawing Fig. 5.
Conclusion: above-mentioned dissolution rate experiment shows that the new Form II I of Dasatinib monohydrate of the present invention has better dissolution rate, proves absolutely that the present invention has scientific meaning.
Annotate: the present invention's concrete technical scheme required for protection is not limited to the concrete combination of the expressed technical scheme of above-described embodiment.Those skilled in the art can carry out various variations and change to the preferred version that the present application is described, and this variation and change can be carried out in the situation of its advantage not deviating from essence of the present invention and scope and do not reduce; Therefore, the present patent application claim covers above-mentioned this variation and change, includes but not limited to equivalent way.
Claims (8)
1. the crystal form II I of a Dasatinib monohydrate, use the Cu-Ka radiation, it is characterized in that: its X-ray powder diffraction, show that with kilsyth basalt 2 θ have diffraction peak at 4.5 ± 0.2,9.1 ± 0.2,11.1 ± 0.2,13.7 ± 0.2,15.1 ± 0.2,17.8 ± 0.2,19.5 ± 0.2,23.1 ± 0.2,25.8 ± 0.2,27.9 ± 0.2,28.5 ± 0.2 places.
2. the crystal form II I of Dasatinib monohydrate as claimed in claim 1 is characterized in that: its X-ray powder diffraction, take kilsyth basalt show 2 θ in the diffraction peak absorption intensity at 13.7 ± 0.2 places as 100%.
3. a method for preparing the crystal form II I of claim 1 or 2 described Dasatinib monohydrates comprises the steps:
(1) Dasatinib is added in an amount of solvent;
(2) heating makes its dissolving;
(3) add while hot suitable quantity of water;
(4) leave standstill down and allow the Dasatinib monohydrate separate out the part crystal,
(5) add remaining water to solution for continuous, crystallization filters, and drying namely gets the Dasatinib monohydrate of crystal form II I.
4. preparation method as claimed in claim 3, wherein, described organic solvent is included in the solvent that can make the Dasatinib dissolving under the heating condition and can dissolve each other with water.
5. preparation method as claimed in claim 4, wherein, described organic solvent is selected from methyl alcohol, acetonitrile, n-propyl alcohol, acetone, dioxane, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), dimethyl formamide.
6. preparation method as claimed in claim 5, wherein, described organic solvent is selected from methyl alcohol, acetonitrile, acetone, dimethyl formamide.
7. pharmaceutical composition, said composition contains claim 1 or the crystal form II I of 2 described Dasatinib monohydrates and the carrier of pharmaceutically accepting of significant quantity on the pharmacology.
8. the purposes of the crystal form II I of Dasatinib monohydrate as claimed in claim 1 or 2 in the medicine of preparation treatment cancer.
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| CN105408329A (en) * | 2013-07-25 | 2016-03-16 | 巴斯夫欧洲公司 | Salts of dasatinib in crystalline form |
| WO2019209908A1 (en) | 2018-04-25 | 2019-10-31 | Johnson Matthey Public Limited Company | Crystalline forms of dasatinib |
| CN111303142A (en) * | 2020-04-01 | 2020-06-19 | 上海博氏医药科技有限公司 | Preparation method of dasatinib monohydrate |
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