CN103059013B - Crystal formation of Dasatinib monohydrate and preparation method thereof - Google Patents
Crystal formation of Dasatinib monohydrate and preparation method thereof Download PDFInfo
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- CN103059013B CN103059013B CN201110316498.9A CN201110316498A CN103059013B CN 103059013 B CN103059013 B CN 103059013B CN 201110316498 A CN201110316498 A CN 201110316498A CN 103059013 B CN103059013 B CN 103059013B
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Abstract
The present invention relates to technical field of pharmaceuticals, be specifically related to crystalline form I II, preparation method and the pharmaceutical composition thereof of Dasatinib monohydrate.The crystalline form I II of Dasatinib monohydrate of the present invention is the most sufficiently stable under the conditions of illumination, high temperature, high humidity and Acceleration study, and its pharmaceutical composition dissolution is good, can stablize under the high temperature conditions.It addition, preparation method of the present invention compared with prior art has easy and simple to handle, quality controllable advantage.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, be specifically related to crystalline form I II, preparation method and the pharmaceutical composition thereof of Dasatinib monohydrate.
Background technology
Dasatinib monohydrate, molecular formula C22H26ClN7O2S.H2O, molecular weight 506.02, CAS863127-77-9.Trade name SPRYCEL, is a kind of oral TYR inhibitors of kinases researched and developed by BMS company, for Adult chronic's myelogenous leukemia (CML), it may also be used for the diseases such as the acute lymphoblastic leukemia for the treatment of Philadelphia Chromosome Positive.Its chemical name is N-(2-chloro-6-aminomethyl phenyl)-2-[[6-[4-(2-ethoxy)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides, and chemical constitution is as follows:
Chinese patent CN200580011916.6 (hereinafter referred " 916 ") file is recorded a kind of crystalline form of Dasatinib monohydrate, and the crystalline form of two kinds of solvates, and has disclosed the preparation method of corresponding crystalline form.Wherein the preparation method of crystalline state monohydrate is to add 22 times of ethanol and 3 times of water to Dasatinib anhydride, it is heated to 75 DEG C of dissolvings (or filtration), and keep being completely dissolved to obtain at 75-80 DEG C, then the water of 8 times amount is added, and ensure that the speed that water adds is maintained between 75-80 DEG C, it is cooled to 75 DEG C, adds the crystal seed of monohydrate, be cooled to 70 DEG C and keep about 1 hour at 70 DEG C.Being cooled to 5 DEG C from 70 DEG C in 2 hours, and keep at least 2 hours at 0-5 DEG C, filter, washing, drying under reduced pressure obtains.In terms of practical operation, Dasatinib anhydride is difficult to dissolve in the ethanol solution of patent consumption, even if the most also cannot realize being completely dissolved, and needs pre-add crystal seed just available required crystal form.Cooling process is complicated, it is difficult to controlling, energy resource consumption is the biggest.
CN201019026056.3 (hereinafter referred " 056 ") file records the crystalline form I of Dasatinib monohydrate and the polymorph II of Dasatinib, and discloses the preparation method of corresponding crystalline form.Wherein the crystalline form I of Dasatinib monohydrate is to add in dimethylformamide or dimethyl sulfoxide by Dasatinib anhydride, heating for dissolving, then the mixed solvent system of a kind of water and organic solvent is dripped, wherein organic solvent is that Dasatinib is insoluble or sl. sol. one or more mixed solvent, after insulation, the lower slow cooling of stirring, to 0-5 DEG C, makes solid separate out completely and growing the grain, filter, be dried to obtain the Dasatinib monohydrate of crystalline form I.It will be apparent that the crystal mass obtained under this complex system is difficult to control, and by bringing the organic liquid waste being difficult to process in a large number during industrialized production, bring immense pressure to environmental conservation.
For molecular structure is identical but medicine that crystal form is different, it likely has different bioavailability, dissolubility, rate of dissolution, chemical physical stability and mobility.These character can directly affect crude drug and the process of preparation or production.Such as: acicular crystal is because carrying a lot of electrostatic, thus seems the most viscous.Therefore the polymorphic of medicine has great importance for quality, safety and the effectiveness of pharmaceutical preparation.
Pharmacy value in view of Dasatinib monohydrate, although the crystal form of Dasatinib monohydrate is it has been reported that but still in the urgent need to a kind of high specific surface area, the Dasatinib monohydrate crystal being prone to industrialized production of stable in properties.Because obtaining that purity is excellent, having and determine that very much crystal form and fabulous this compound of repeatability are important, its result is to present the valuable characteristic of tool in terms of preparation, and sufficiently stable so that it can with long-time storage not particular/special requirement to temperature, light, humidity or oxygen level.
Summary of the invention
The present inventor is through substantial amounts of research, it is surprised to find the new crystal form of Dasatinib monohydrate, successfully overcome the various defects in producing at present, obtain high specific surface area, the Dasatinib monohydrate crystal being prone to industrialized production of stable in properties, referred to as the crystalline form I II of Dasatinib monohydrate.Described crystal form is especially showing valuable characteristic in terms of preparation.
The purpose of the present invention, it is provided that the new crystalline form I II of the novel polymorphic thing of a kind of Dasatinib monohydrate, i.e. Dasatinib monohydrate.
Specifically the invention provides the crystalline form I II of a kind of Dasatinib monohydrate, its X-ray powder diffraction spectrum is substantially consistent with shown in Fig. 1, has diffraction maximum with the 2 θ angles that degree represents 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.
Compared with the monohydrate of the Dasatinib described in " 916 " file, the crystalline form I II of Dasatinib monohydrate has more preferable physicochemical property, and stability is more preferable, and has dissolution faster.
It is a further object to provide the preparation method of the new crystalline form I II of Dasatinib monohydrate, include but not limited to following:
(1) Dasatinib is added in appropriate solvent；Solvent include methanol, acetonitrile, normal propyl alcohol, isopropanol, acetone, dioxane, N-Methyl pyrrolidone, dimethyl sulfoxide, dimethylformamide etc. can dissolve in a heated condition Dasatinib and can be miscible with water solvent.Dasatinib is different with the different solubility of solvent with volume ratio from the weight of solvent, so that Dasatinib is completely dissolved as target.
(2) heating makes it dissolve；Heating-up temperature the most under reflux conditions can be dissolved from room temperature to solvent refluxing, and the quantity of solvent so used is minimum.
(3) suitable quantity of water is added while hot；The consumption of water is different with the difference of solvent species, and the amount of addition has just occurred that with solution muddiness becomes clear as standard the most immediately.
(4) standing lower slow cooling and separate out partial crystals by Dasatinib monohydrate, cooling rate is no faster than 30 DEG C/h；Preferably cooling rate is no faster than 20 DEG C/h, and more preferably cooling rate is not higher than 10 DEG C/h.
(5) in solution, remaining water is continuously added, crystallize, filters, is dried, obtains the Dasatinib monohydrate of crystal formation III.The product yield so obtained is higher, and can improve production efficiency.
Although a kind of crystal form of prior art " 916 " file known Dasatinib monohydrate optionally can be manufactured by complicated operation with water mixed solvent with by ethanol or other alcohol, but surprisingly can dissolve Dasatinib the solvent miscible with water mixture with water with methanol or other heating and can be obtained the crystallization of different crystal forms by suitable process with selectivity.
Compared with, the crystal form of Dasatinib monohydrate described in " 916 " file is compared, and the crystal purity that the present invention obtains is higher, more homogeneous, operates easier, and process repeatability is more preferable, is more suitable for preparation and uses.
Compared with the crystalline form I having recorded Dasatinib monohydrate in " 056 " file, the dicyandiamide solution of complexity is used in the preparation of the crystalline form I of Dasatinib monohydrate, it is difficult to controls the purity of crystal, is also unfavorable for the removal of environmental conservation and residual solvent.And single solvent and water are only used in the preparation of the crystalline form I II of Dasatinib monohydrate, it is more suitable for the recycling of solvent, decreases the reduction of the pollution to environment, beneficially industrial production cost.
Third object of the present invention is to provide medicine and the compositions of pharmaceutic adjuvant reaching the crystalline form I II containing above-mentioned Dasatinib monohydrate.This pharmaceutical composition contains the Dasatinib monohydrate 1～500mg of crystalline form I II, it is preferable that containing Dasatinib about 20mg, 50mg, 70mg, 100mg crystal form thing III.The crystal form thing III of the present invention can add suitable pharmaceutic adjuvant, makes various dosage form, to meet the needs of all kinds of patient.
The crystalline form I II of described Dasatinib monohydrate application in preparation treatment cancer drug.
X-powder diffraction test instrunment involved in the present invention is D8 advence diffractometer (Brooker company limited of Germany)；Copper target, graphite monochromator, tube voltage 40Kv, tube current 40mA, scanning speed 0.2S/ walk
Involved in the present invention have related substance testing conditions and method be: according to high effective liquid chromatography for measuring (2005 editions two annex of Chinese Pharmacopoeia)
Condition determination: be filler with octadecylsilane chemically bonded silica；Aqueous phase A is 0.01mol/L sodium dihydrogen phosphate, 0.1% triethylamine, and phosphoric acid adjusts pH value to 3.0, and organic facies B is acetonitrile, flow velocity 1.0ml/min；Detection wavelength is 220nm；According to the form below carries out gradient elution, and number of theoretical plate is calculated by Dasatinib peak and is not less than 2000；Dasatinib should meet the requirements with the separating degree at other impurities peak.
Content assaying method: take this product, accurately weighed, add that flowing is mutually ultrasonic makes dissolving dilution make in every 1ml the solution containing about 50 μ g, precision measures 20 μ l, injects chromatograph of liquid, records chromatogram.Separately take Dasatinib reference substance appropriate, accurately weighed, adding flowing and make dissolving mutually and make in every 1ml the solution containing about 50 μ g, being measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Dissolution determination method involved in the present invention takes sample, according to dissolution method (2005 editions two annex XC the second methods of Chinese Pharmacopoeia), with pH4.0 acetate buffer solution as dissolution medium, rotating speed is 60 turns per minute, operate in accordance with the law, carry out when 10min, 15min, 30min, 45min, 60min respectively taking a little and carry out ultraviolet detection (λ=320).
The Dasatinib monohydrate stable crystal formation experiment of crystal form thing III
1, illumination experiment
Operation: take this product and be laid in culture dish (about 2mm thickness) in right amount, places 10 days under the conditions of being placed in 4500Lx scholar's 500Lx strong illumination, in the 5th day, sampling detection in 10 days,
2, high temperature experiment
Take this product and be laid in culture dish (about 2mm thickness) in right amount, be placed in the calorstat of 60 DEG C placement 10 days, in sampling detection in the 5th, 10 days
3, high humidity experiment
Take this product and be laid in culture dish (about 2mm thickness) in right amount, place 10 days under conditions of being placed in 25 DEG C of scholars of room temperature 2 DEG C, relative humidity RH90% scholar 5%, in sampling detection in the 5th, 10 days
4, Acceleration study
This product presses commercially available back, under the conditions of putting temperature 40 DEG C ± 2 DEG C, relative humidity RH75% ± 5%, places 6 months, samples once the 1st, 2,3,6 the end of month,
From above-mentioned experimental data, the Dasatinib hydrate novel crystalline form I II of the present invention is the most sufficiently stable under the conditions of illumination, high temperature, high humidity and Acceleration study.
The preparation high temperature experiment of the Dasatinib monohydrate of crystal form thing III
Experimental technique:
The crystal form of above-mentioned different schemes is prepared as solid preparation according to same formulation method (supplementary product kind, consumption are identical), is placed in the calorstat of 60 DEG C placement 10 days, in the 0th, 5,10 days sampling and measuring, compared with 0 day.Measurement result see table.
High temperature experimental result
Experiment conclusion: above-mentioned experiment shows, the new crystalline form I II of Dasatinib monohydrate of the present invention can prepare the more outstanding product of quality (dissolution is more preferable, and product is more stable).
Accompanying drawing illustrates:
The XRPD figure of Fig. 1 Dasatinib of the present invention monohydrate crystalline form I II
Fig. 2 Dasatinib of the present invention monohydrate crystalline form I II strong illumination XRPD of 10 days schemes；
Fig. 3 Dasatinib of the present invention monohydrate crystalline form I II high temperature XRPD of 10 days schemes；
The high humidity XRPD of the 10 days figure of Fig. 4 Dasatinib of the present invention monohydrate crystalline form I II；
Fig. 5 Dasatinib of the present invention monohydrate crystalline form I II tablet formulation and patent " 916 " tablet formulation stripping curve comparison diagram.
Detailed description of the invention
The following example is used for illustrating the present invention, but should not be construed to limitation of the present invention.
Embodiment 1:
The preparation of Dasatinib monohydrate crystalline form I II
Taking in the methanol that 28g Dasatinib adds 2000ml, be heated to dissolving, filtered while hot one time under stirring, in filtrate, stirring is lower adds 1400ml water, stop stirring, Temperature fall, slowly separate out fine crystals, it is stirred at room temperature down after 3 hours and adds 600ml water, add stopping stirring, place crystallize.The white crystal that sucking filtration separates out, a small amount of methanol washs, and is vacuum dried at 60 DEG C, and phosphorus pentoxide helps dry, obtains product 23g, White crystal powder.
Embodiment 2:
The preparation of Dasatinib monohydrate crystalline form I II
Take in the acetone that 10g Dasatinib adds 1000ml, be heated to backflow under stirring and dissolve, filtered while hot one time, in filtrate, stirring is lower adds 500ml water, stop stirring, Temperature fall, slowly separate out fine crystals, it is stirred at room temperature down after 4 hours and adds 500ml water, add stopping stirring, place crystallize.The white crystal that sucking filtration separates out, washs on a small quantity, is vacuum dried at 60 DEG C, and phosphorus pentoxide helps dry, obtains product 8.4g, White crystal powder.
Embodiment 3:
The preparation of Dasatinib monohydrate crystalline form I II
Taking in the dimethylformamide that 10g Dasatinib adds 50ml, be heated to 70 DEG C of dissolvings, filtered while hot one time under stirring, in filtrate, stirring is lower adds 75ml water, stopping stirring, Temperature fall, to slowly separating out fine crystals, it is stirred at room temperature down and adds 30ml water, add stopping stirring, place crystallize.The white crystal that sucking filtration separates out, washs on a small quantity, is vacuum dried at 60 DEG C, and phosphorus pentoxide helps dry, obtains product 7.3g, White crystal powder.
Embodiment 4:
The preparation of Dasatinib monohydrate crystalline form I II
Take in the acetonitrile that 5g Dasatinib adds 300ml, be heated to backflow under stirring and dissolve, filtered while hot one time, in filtrate, stirring is lower adds 100ml water, stopping stirring, Temperature fall, to slowly separating out fine crystals, it is stirred at room temperature down and adds 50ml water, add stopping stirring, place crystallize.The white crystal that sucking filtration separates out, washs on a small quantity, is vacuum dried at 60 DEG C, and phosphorus pentoxide helps dry, obtains product 2.8g, White crystal powder.
Embodiment 5
The prescription of Dasatinib tablet, preparation technology and dissolution comparative experiments
Preparation preparation and dissolution experiment is carried out respectively by the Dasatinib monohydrate crystalline form I II of the present invention and the crystal form prepared according to " 916 " document addresses.
Sheet heart prescription:
| Dasatinib monohydrate | 0.518g |
| Lactose | 0.67g |
| Microcrystalline Cellulose | 0.67g |
| Hypromellose | 0.11g |
| Cross-linking sodium carboxymethyl cellulose | 0.04g |
| 30% ethanol | In right amount |
| Magnesium stearate | 0.01g |
| System altogether | 100 |
Preparation method: Dasatinib pulverized 200 mesh sieves；The principal agent of recipe quantity mixes with the cross-linking sodium carboxymethyl cellulose equivalent method of progressively increasing of lactose, microcrystalline Cellulose, hydroxy propyl cellulose and 1/2 recipe quantity, crosses 80 mesh sieve and i.e. obtains mixed powder 3 times.Being wetting agent soft material with 30% ethanol, 24 mesh sieves are pelletized, and 60 DEG C are dried, 24 mesh sieve granulate, add recipe quantity magnesium stearate and residue cross-linking sodium carboxymethyl cellulose, mix homogeneously.Regulation tablet weight and pressure, tabletting.
Carrying out preparation preparation and dissolution experiment respectively by the Dasatinib monohydrate crystalline form I II of the present invention and the crystal form prepared according to " 916 " document addresses, result is as follows.
Dissolution comparative experiments
According to aforementioned dissolution determination method, carrying out dissolution determination, the dissolution data of Dasatinib monohydrate crystalline form I II is determined as follows respectively with document crystal formation dissolution data:
Table 1: the dissolution of Dasatinib monohydrate crystalline form I II
Table 2: the dissolution of Dasatinib monohydrate " 916 " crystal form
Tablets compares with patent " 916 " tablet formulation stripping curve sees accompanying drawing Fig. 5.
Conclusion: above-mentioned Dissolution experiments shows, the new crystalline form I II of Dasatinib monohydrate of the present invention has more preferable dissolution, absolutely proves that the present invention has scientific meaning.
Note: the present invention concrete technical scheme required for protection, is not limited to the concrete of the technical scheme expressed by above-described embodiment and combines.Those skilled in the art can carry out various change and change to the preferred version that the present application describes, and this change and change can carried out without departing substantially from spirit and scope of the present invention and in the case of not reducing its advantage；Therefore, the present patent application claim covers above-mentioned this change and change, includes but not limited to equivalent way.
Claims (5)
1. the crystal formation III of a Dasatinib monohydrate, uses Cu-Ka radiation, and its X-ray powder spreads out
Penetrate collection of illustrative plates, with degree represent 2 θ 4.5 ± 0.2,9.1 ± 0.2,11.1 ± 0.2,13.7 ± 0.2,15.1 ± 0.2,
Diffraction maximum is had at 17.8 ± 0.2,19.5 ± 0.2,23.1 ± 0.2,25.8 ± 0.2,27.9 ± 0.2,28.5 ± 0.2,
It is characterized in that: 2 θ diffraction maximum absorption intensity at 13.7 ± 0.2 is 100%.
2. the method preparing the crystal formation III of Dasatinib monohydrate described in claim 1, including such as
Lower step:
(1) Dasatinib is added in appropriate solvent；
(2) heating makes it dissolve；
(3) suitable quantity of water is added while hot；
(4) Dasatinib monohydrate is allowed to separate out partial crystals under standing,
(5) in solution, remaining water is continuously added, crystallize, filter, be dried, obtain crystal formation III reaches sand
For Buddhist nun's monohydrate；
Wherein, described solvent selected from methanol, acetonitrile, normal propyl alcohol, acetone, dioxane, N-methylpyrrole
Alkanone, dimethyl sulfoxide, dimethylformamide.
3. preparation method as claimed in claim 2, wherein, described solvent selected from methanol, acetonitrile, third
Ketone, dimethylformamide.
4. a pharmaceutical composition, reaches sand described in the claim 1 that said composition contains pharmacologically effective dose
For the crystal formation III of Buddhist nun's monohydrate and the carrier that pharmaceutically accepted.
5. the crystal formation III of Dasatinib monohydrate as claimed in claim 1 is at the medicine of preparation treatment cancer
In purposes.
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| 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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| CN102086195A (en) * | 2011-01-28 | 2011-06-08 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof |
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| PL2508523T5 (en) * | 2007-10-23 | 2020-08-10 | Teva Pharmaceutical Industries Ltd. | Polymorphs of dasatinib and process for preparation thereof |
| WO2010067374A2 (en) * | 2008-12-08 | 2010-06-17 | Hetero Research Foundation | Polymorphs of dasatinib |
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| CN101891738A (en) * | 2010-02-08 | 2010-11-24 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorph and preparation method and medical composite thereof |
| CN102086195A (en) * | 2011-01-28 | 2011-06-08 | 南京卡文迪许生物工程技术有限公司 | Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof |
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