CN102086195A - Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof - Google Patents
Dasatinib polymorphic substance as well as preparation method and medicinal composition thereof Download PDFInfo
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Abstract
The invention discloses a dasatinib polymorphic substance. In addition, the invention also discloses a preparation method and a medicinal composition of the dasatinib polymorphic substance. The dasatinib polymorphic substance provided by the invention has the advantages of good physicochemical property and good stability, is more suitable for industrial scale preparation, and the like.
Description
Technical field
The present invention relates to the polymorphic form of medical compounds, more particularly, relate to the polymorphic form of Dasatinib, in addition, the invention still further relates to the preparation method and the pharmaceutical composition thereof of this polymorphic form.
Background technology
Dasatinib, trade(brand)name SPRYCEL
TM, be a kind of oral tyrosine kinase inhibitor by BMS company research and development, the chronic myelogenous leukemia (CML) that is used to be grown up 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:
Bristol-Myers Squibb Co has put down in writing five kinds of crystalline form of Dasatinib and has disclosed the preparation method of corresponding crystalline form in Chinese patent application-application number CN200580011916.6 file (open day is on June 13rd, 2007).The preparation method who instructs in this document is:
Monohydrate: adding 48g Dasatinib, 1056ml (22ml/g) ethanol and 144ml water are heated to 75 ℃ of dissolving purification filterings and transfer in the receptor.Mixture flushing dissolution reactor and transfer line with 43ml ethanol and 5ml water.Heated solution to 75～80 ℃ dissolve it fully, and heating 384ml water also remains between 75～80 ℃ solution temperature.Be cooled to 75 ℃ and add monohydrate crystal seeds (preferably), be cooled to 70 ℃ of insulation 1h, at 2h internal cooling to 5 ℃ and between 0～5 ℃, be incubated 2h, filter slurry, the mixture washing leaching cake of usefulness 96ml ethanol and 96ml water ,≤50 ℃ of drying under reduced pressure get 41g.
Butanols solvate: under reflux (116～118 ℃), under the concentration of about 1g/25ml solvent, Dasatinib is dissolved in the 1-butanols, makes the crystallization butanols solvate of Dasatinib.This butanols solvate crystallizes out from solution when cooling.Filter, with butanols washing, after drying.
Alcohol solvent compound: in the 100ml round-bottomed flask, add the 5D of 4g (10.1mmol), the 7B of 6.6g (50.7mmol), the DIPEA of 80ml propyl carbinol and 2.61g (20.2mmol).The gained slurry is heated to 120 ℃ of insulation 4.5h postcooling to 20 ℃ and stirs and spend the night.Crystallization is filtered, and (2 * 10ml) washings get the white crystals product to wet cake with propyl carbinol.The gained wet cake is turned back in the 100ml reactor 200 degree (proof) ethanol of the 56ml that packs into (12ml/g).Add 25ml ethanol again at 80 ℃, in this mixture, add 10ml water and make its quick dissolving.Remove heating, observe crystallization at 75～77 ℃.The crystallization slurry further is cooled to 20 ℃ then to be filtered.Wet cake 10ml ethanol: water (1: 1) washs once, then with the washing of 10ml normal heptane once.Drying got the material that 3.55g only contains 0.19% water in 17 hours under 60 ℃/30in Hg.
The N-6 of pure form: to compound 5D (175.45,0.445mol) and the hydroxyethyl piperazine (289.67g, 2.225mol) add in the mixture in NMP (1168ml) DIPEA (155ml, 0.89mmol).Suspension is obtained solution at 110 ℃ of heating 25min, be cooled to about 90 ℃ then.With the gained hot solution be added drop-wise to hot water (80 ℃, 8010ml) in 80 ℃ of insulated and stirred 15 minutes, after slowly cool to room temperature.Solid is collected in vacuum filtration, and water (2 * 1600ml) washings, dry in 55～60 ℃ of following vacuum, obtain the 192.45g compound.
The T1H1-7 of pure form (pure form and pharmaceutically acceptable carrier): the Dasatinib monohydrate is heated under the dehydration temperaturre and makes being higher than.
The method of application documents CN200580011916.6 instruction can't reduce related substance in the product effectively to improve the quality of product in the crystal formation preparation process.
The inventor has submitted a kind of polymorphic form Chinese patent application of Dasatinib monohydrate on February 8th, 2010, application number CN201019026056.3, use DMF or DMSO dissolving Dasatinib, thereby water or aqueous organic solvent are forced and are analysed the polymorphic form that obtains a kind of stable Dasatinib monohydrate then.
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 can directly influence the processing or the production of bulk drug and preparation, and can influence stability of formulation, solubleness and bioavailability.Therefore, the polymorphic of medicine has great importance for quality, security and the validity of pharmaceutical preparation.For Dasatinib, this area exists such demand: the novel polymorphic that is suitable for commercial scale production, physicochemical property excellence.
Summary of the invention
The present inventor has been surprisingly found out that new Dasatinib polymorph through a large amount of research, has successfully solved the deficiency that prior art exists, and it has physico-chemical property excellence, a good stability, be more suitable for advantage such as industrially scalable preparation.
The purpose of this invention is to provide new Dasatinib polymorph.
Another object of the present invention provides the preparation method of above-mentioned novel polymorphic thing.
The 3rd purpose of the present invention provides the medicinal compositions that contains above-mentioned novel polymorphic thing.
Specifically, the invention provides a kind of Dasatinib polymorph III that contains a part crystal water and do not contain other organic solvent.
The polymorphic form III of Dasatinib provided by the present invention uses the Cu-Ka radiation, and among its X-ray diffraction (XRPD) figure, 2 θ that show with kilsyth basalt are 9.1 ± 0.1, and 27.9 ± 0.1, and there is diffraction peak at 28.5 ± 0.1 places; Particularly 9.1 ± 0.1,11.1 ± 0.1,13.7 ± 0.1,15.1 ± 0.1,17.9 ± 0.1,18.3 ± 0.1,19.1 ± 0.1,19.5 ± 0.1,22.2 ± 0.1,23.1 ± 0.1,23.5 ± 0.1,24.3 ± 0.1,25.8 ± 0.1,27.9 there is diffraction peak at ± 0.1 and 28.5 ± 0.1 places, as the diffraction peak that has among the X-RPD figure listed at table 1 and similar relative diffracted intensity thereof; Its typical X-RPD collection of illustrative plates is seen Fig. 1.
The X-RPD diagram data of table 1 Dasatinib polymorph III of the present invention
| The peak numbering | 2θ | The Flex width | The d-value | Intensity | I/ |
| 1 | 4.540 | 0.188 | 19.4473 | 1065 | 16 |
| 2 | 9.120 | 0.188 | 9.6887 | 2041 | 30 |
| 3 | 11.120 | 0.212 | 7.9502 | 4165 | 60 |
| 4 | 12.260 | 0.118 | 7.2134 | 743 | 11 |
| 5 | 13.740 | 0.212 | 6.4396 | 2938 | 43 |
| 6 | 15.140 | 0.212 | 5.8471 | 3148 | 46 |
| 7 | 16.100 | 0.047 | 5.5005 | 704 | 11 |
| 8 | 17.880 | 0.235 | 4.9568 | 6950 | 100 |
| 9 | 18.300 | 0.212 | 4.8439 | 1861 | 27 |
| 10 | 19.060 | 0.188 | 4.6525 | 2602 | 38 |
| 11 | 19.460 | 0.235 | 4.5577 | 4429 | 64 |
| 12 | 20.140 | 0.165 | 4.4054 | 806 | 12 |
| 13 | 21.160 | 0.188 | 4.1952 | 811 | 12 |
| 14 | 22.160 | 0.141 | 4.0081 | 1606 | 24 |
| 15 | 23.060 | 0.212 | 3.8537 | 2509 | 37 |
| 16 | 23.460 | 0.141 | 3.7889 | 2831 | 41 |
| 17 | 24.340 | 0.212 | 3.6539 | 1587 | 23 |
| 18 | 24.680 | 0.165 | 3.6043 | 911 | 14 |
| 19 | 24.940 | 0.188 | 3.5673 | 1225 | 18 |
| 20 | 25.780 | 0.188 | 3.4529 | 1667 | 24 |
| 21 | 27.920 | 0.188 | 3.1929 | 2155 | 32 |
| 22 | 28.520 | 0.212 | 3.1271 | 1025 | 15 |
| 23 | 30.080 | 0.118 | 2.9684 | 775 | 12 |
| 24 | 33.920 | 0.071 | 2.6406 | 789 | 12 |
| 25 | 34.580 | 0.165 | 2.5917 | 1006 | 15 |
| 26 | 35.040 | 0.235 | 2.5587 | 997 | 15 |
The polymorphic form III of Dasatinib provided by the present invention, between 80～130 ℃, particularly (122.17 ℃) have endotherm(ic)peak about 122 ℃ in the scope of first endotherm(ic)peak in its DSC scanning; The scope that its second endotherm(ic)peak is maximum endothermic transition particularly has endotherm(ic)peak about 281 ℃ (281.83 ℃) between 280～285 ℃.The typical DSC collection of illustrative plates of Dasatinib polymorph III of the present invention is seen Fig. 2, and typical TGA collection of illustrative plates is seen Fig. 3.
In addition, the infrared absorption pattern that Dasatinib polymorph III of the present invention records with the KBr compressing tablet is about: 3464.39cm
-1, 3211.60cm
-1, 3013.97cm
-1, 2954.56cm
-1, 2824.32cm
-1, 1682.81cm
-1, 1634.18cm
-1, 1612.84cm
-1, 1584.72cm
-1, 1305.92cm
-1, 1291.54cm
-1, 1041.40cm
-1, 1000.46cm
-1There is absorption peak at the place; See Fig. 4.
In embodiments of the invention, the invention provides Dasatinib polymorph III, this method comprises the steps:
(1) Dasatinib is added in the entry; Wherein: the volume of water and Dasatinib and weight ratio are usually greater than 1: 1 (ml: g); Preferably, be selected from: the volume of water and Dasatinib and weight ratio were more than or equal to 5: 1 (ml: g); Most preferably, the volume of water and Dasatinib and weight ratio are 5: 1 to 15: 1 (ml: g);
(2) heating under agitation; Heating temperature can be room temperature to reflux temperature; Preferably be selected from: Heating temperature be 40 ℃ to reflux temperature; Most preferably be selected from: Heating temperature be 80 ℃ to reflux temperature;
(3) insulation growing the grain; Rearing crystal time can be at 10 minutes to 72 hours, preferred 1 hour to 48 hours; Most preferably at 2 hours to 6 hours;
(4) reduce to the room temperature solid collected by filtration, and dry, preferably, help driedly with Vanadium Pentoxide in FLAKES, at 50 ℃ ,-0.095MPa reduced vacuum is dry more than 12 hours.
In the present invention, X-powdery diffractometry testing tool and test condition involved in the present invention are: anode changes target x-ray diffractometer D/max-2500/PC type (Japan is of science); It is 3～40 ° of 0.3mm, 5 °/min of sweep velocity, sweep limits that copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, divergent slit and anti-scatter slit are 1 °, reception slit.
DSC testing tool and test condition involved in the present invention are: U.S. Perkin ElmerDiamond DSC; With the heating of 10 ℃/min speed, from 25 ℃ to 300 ℃.
TGA testing tool and test condition involved in the present invention are: U.S. Perkin ElmerThermal Analysis Pyris 1TGA; With the heating of 10 ℃/min speed, from 25 ℃ to 500 ℃.
Related substance testing conditions and method involved in the present invention are: measure according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability
With octadecylsilane chemically bonded silica is weighting agent; (0.2% triethylamine is with phosphorus acid for adjusting pH value to 2.5)-methyl alcohol (45: 55) is moving phase with the 0.05mol/L potassium primary phosphate; Detect wavelength 230nm; Theoretical plate number is calculated by the Dasatinib peak should be not less than 2000.The resolution of Dasatinib peak and adjacent impurity peaks should meet the requirements.
The assay method sample thief adds the moving phase dissolving and makes the solution that contains 0.5mg among every 1ml, measures 20 μ l, injects liquid chromatograph respectively, and the record color atlas is to 6 times of principal constituent peak retention time.
The characteristic of Dasatinib polymorph III
One, solvability: test with reference to two notes on the use of Chinese Pharmacopoeia version in 2000.
Method: it is an amount of that precision takes by weighing Dasatinib polymorph III, slowly adds certain amount of solvent, and powerful jolting was 30 seconds every 5 minutes, observes the dissolving situation in 30 minutes, the results are shown in Table 2.
Table 2 Dasatinib polymorph III solubility test
Two, stability
L, exposure experiments to light
Dasatinib polymorph III is evenly shared to uncovered culture dish, thickness≤5mm, adjustable range, making intensity of illumination is 4500 ± 500Lx, detects respectively at sampling in 5,10 days, and contrasts with 0 day result.The results are shown in Table 3.
Table 3 exposure experiments to light (4500 ± 5001x)
Annotate: 23～25 ℃ of temperature variation; Relative humidity variations 56%～64%
2, high temperature test
Dasatinib polymorph III raw material is positioned in the clean vial of sealing, places 60 ℃ of thermostatic drying chambers, detect, and contrast with 0 day result respectively at sampling in 5,10 days.The results are shown in Table 4.
Table 4 high temperature test (60 ℃)
Annotate: relative humidity variations 56%～65%
3, high wet test
Dasatinib polymorph III raw material is evenly shared to uncovered culture dish, and thickness≤5mm places room temperature (about 25 ℃), relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, measure respectively at sampling in 5,10 days, and contrast with 0 day result.The results are shown in Table 5.
The high wet test of table 5 (room temperature, relative humidity 75 ± 5%)
Annotate: 23～26 ℃ of temperature variation
4, accelerated test
The raw material of Dasatinib polymorph III is packed with the polyethylene film plastic bag sealing, placed 40 ± 2 ℃, relative humidity is in 75 ± 5% the fixed temperature and humidity incubator, placed six months, respectively at 1,2,3,6 the end of month, sampling detected, and contrasted with 0 month result.The results are shown in Table 6.
Table 6 accelerated test (40 ℃, relative humidity 75% ± 5%)
Experimental result shows that the related substance of Dasatinib polymorph III polymorphic form III under illumination condition that the present invention obtains has a small amount of increase, and content descends to some extent; In high temperature test (60 ℃), outward appearance does not have obvious change but content has more a spot of decline; Crystal form II I of the present invention its outward appearance and content in high wet test all do not have considerable change, and water absorbability is less; Accelerated tests result shows that its physico-chemical property of Dasatinib bulk drug with crystal formation of the present invention is relatively stable.
This product is not observed crystal formation and is changed in long-term reserved sample observing test; Related substance has more a spot of increase, and content has more a spot of decline.Test shows that the crystal habit of this polymorphic III is stable, suitable prolonged preservation.
In addition, polymorphic III weightlessness (water) process occurs between 80 ℃ to 130 ℃, according to TGA scintigram (Fig. 4-2) calculating weightless 3.47% of Dasatinib polymorph III; And this compound is through detecting the limit requirement that the organic solvent residual quantity meets the ICH regulation; The moisture value that Ka Shi moisture method is measured is 3.55%; Comprehensive above-mentioned interpretation shows that Dasatinib polymorph III of the present invention is a monohydrate.
Find by further experiment, crystal form II I of the present invention is placing the closed environment of strong dewatering agent (as discolour silica gel, Vanadium Pentoxide in FLAKES etc.) can progressively lose (part is until whole) crystal water, but this polycrystalline thing that loses partial crystallization water is placed on the state that can progressively return back to a crystal water of crystal form II I of the present invention in the air ambient after for some time again.
In another embodiment of the invention, the invention provides the medicinal compositions that contains one or both and pharmaceutical excipient among the above-mentioned Dasatinib polymorph III, preferably, this medicinal compositions contains Dasatinib polymorph 1～500mg, particularly preferably, contain about 20,50,70, the 100 milligrams of polymorphic forms of Dasatinib.According to the instruction of state of the art, and with reference to the patent that the present invention quoted, medicinal compositions of the present invention can be made into various formulations, and selects suitable pharmaceutical excipient.For example, according to disease to be treated and object, medicinal compositions of the present invention is by oral, parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion), suction spraying, nose, vagina, rectum, hypogloeeis or topical administration; Preferably, be composition for oral liquid, particularly, oral tablet, capsule or granule.Those of ordinary skill in the art can carry out dressing to composition for oral liquid according to the instruction of prior art, for example Chinese patent application CN 101170996A (open day is on April 30th, 2008).
The present invention comprises the medicinal compositions of Dasatinib polymorph, optionally also can contain other therapeutic component, for example, wherein one or more such as ipsapirone, taxol, Docetaxel, cis-platinum, carboplatin, rhuMAb-VEGF, bendamustine, Tarceva, nilotinib, Rituxima, dexamethasone, Revlimid, capecitabine, Exemestane, letrozole, Dacarbazine, ZD6474 and Ipilimumab.
Medicinal compositions of the present invention is once a day or repeatedly per daily dose and administration, and per daily dose is about 5～1000 mg/day, more preferably about 10～500 mg/day.Perhaps, administration every other day, about 10～250 mg/day.
The example that Dasatinib polymorph of the present invention can be used for treating disease and symptom includes but not limited to: transplant rejection, rheumatoid arthritis, multiple sclerosis, enteritis, lupus, graft versus host disease (GVH disease), the hypersensitivity disease that T-is cell-mediated, psoriasis, Hashimoto's struma, cancer (comprises chronic myelogenous leukemia CML, gastrointestinal stromal tumor GIST, small cell lung cancer SCLC, nonsmall-cell lung cancer NSCLC, ovarian cancer, melanoma, mastocyte propagation is sick, gonioma, acute myeloid leukaemia AML, children's's sarcoma, mammary cancer, colorectal carcinoma, carcinoma of the pancreas, prostate cancer etc.), contact dermatitis, anaphylactic disease, asthma, diabetic retinopathy, and chronic obstructive pulmonary disease etc.In addition, under instruction of the present invention, those skilled in the art can determine concrete method and dosage according to prior art, for example, and international application for patent, publication No. WO2004085388A2.
Useful technique effect of the present invention is embodied in: although the report of prior art CN200580011916.6 patent documentation Dasatinib polymorph and preparation method thereof.But the polymorphic form preparation method of the preparation Dasatinib that CN200580011916.6 provides learns that by test the rotating crystal method of this patent documentation instruction is not suitable for the mass-producing stably manufactured.
Prior art CN200580011916.6 patent documentation its preparation method be with Dasatinib join the insoluble,practically alcohols organic solvent of Dasatinib or alcohols organic solvent and water mixed solution under cooling, separate out crystal after (as: alcoholic solvent methyl alcohol, ethanol, butanols etc.) heating for dissolving.
1, because in the water-soluble hardly or alcohol organic solvent of Dasatinib, even also need to use a large amount of solvents under heating state, so it is loaded down with trivial details to change brilliant technology, controllable product quality is poor, is not suitable for the mass-producing stably manufactured.
When 2, in patent document CN200580011916.6, preparing Dasatinib monohydrate crystal formation, need to add crystal seed, though it emphasizes " crystal seed concerning obtaining monohydrate not necessarily; crystallization control better ", but still can illustrate that the collimation of its technology and circulation ratio are good inadequately.
3, in patent document CN200580011916.6, learn by experiment than the stability performance of the crystal formation thing III of the present invention preparation by the prepared crystal form A stability of its condition poor;
4, in existing crystal formation preparation method, all need add organic solvent.And well-known, organic solvent all has more or less toxicity to human body, and is unfriendly to environment simultaneously;
The preparation method of patent document CN200580011916.6 and existing Dasatinib polymorph has complex process in a word, be difficult to avoid organic residual and cause a series of shortcoming such as environmental pollution.
Yet it is simple to the invention provides technology, the purity height, and the Dasatinib polymorph of environment amenable suitable suitability for industrialized production and preparation method have overcome problems of the prior art.
The present invention is to the polymorphic form of Dasatinib, and its crystallization condition fully takes into account the deficiency of aforesaid existing method, has adopted the preparation method who more rationally reaches science:
1, preparation technology of the present invention is simple, and is simple to operate, quality controllable, the yield height, and technology collimation and favorable reproducibility are fit to technology production;
2, the prepared polymorphic form good stability of preparation technology of the present invention is suitable for long-term seasoning;
3, the stability of polymorphic III disclosed in this invention in water disclosed polymorphic A good stability in rupture test in the patent CN200580011916.6, this makes polymorphic form of the present invention be of value to the requirement of preparation process and preparation prolonged preservation more; In addition, the experiment proved that Dasatinib polymorph III of the present invention is after making preparation, its crystal formation remains unchanged basically, crystal formation stable outstanding, and the related substance that detects bulk drug contained in the preparation do not increase, and is more suitable for as medicine.
4, polymorphous preparation method of the present invention not with an organic solvent, environmentally friendly, more reduced simultaneously cost;
Above advantage makes the present invention be of value to environmentally friendly by using, and there do not have toxic pure water preparation to obtain to be stable, is fit to medicinal a kind of Dasatinib polymorph.
Description of drawings
Fig. 1 is the typical X RPD figure of Dasatinib polymorph III of the present invention.
Fig. 2 is the DSC scintigram of Dasatinib polymorph III of the present invention.
Fig. 3 is respectively the TGA scintigram of Dasatinib polymorph III of the present invention.
Fig. 4 is the IR infrared absorpting light spectra of Dasatinib polymorph III of the present invention.
Fig. 5 is the stripping curve of the capsule formula 1 of Dasatinib polymorph III of the present invention.
Fig. 6 is the stripping curve of the capsule formula 2 of Dasatinib polymorph III of the present invention.
Fig. 7 is the stripping curve of the tablet formulation 1 of Dasatinib polymorph III of the present invention.
Fig. 8 is the stripping curve of the tablet formulation 2 of Dasatinib polymorph III of the present invention.
Embodiment
Add Dasatinib 16g in reaction flask, purified water 160ml is warming up to backflow under stirring, and growing the grain 3 hours is reduced to the room temperature suction filtration naturally, and filter cake is with suitable quantity of water drip washing and drain.Filter cake reduces pressure in about 50 ℃, and (0.095MPa) drying helps dried with Vanadium Pentoxide in FLAKES.Get the 15.4g white solid.Yield: 96.3%.
Add Dasatinib 10g in reaction flask, purified water 90ml is warming up to backflow under stirring, and growing the grain 4 hours is reduced to the room temperature suction filtration, and filter cake is with suitable quantity of water drip washing and drain.Filter cake reduces pressure in about 50 ℃, and (0.095MPa) drying helps dried with Vanadium Pentoxide in FLAKES.Get the 9.8g white solid.Yield: 98.0%.
The prescription of Dasatinib capsule and preparation technology:
With several vehicle above-mentioned Dasatinib polymorph III is made the capsule preparations that contains 50mg as follows.
The manufacture method that contains the capsule of Dasatinib polymorph III is that preceding four kinds in the above-mentioned vehicle are added water and make softwood in right amount with Dasatinib polymorph III, carry out drying after softwood made wet granular, insert capsule shell after dried particle and Magnesium Stearate mix and promptly obtain the Dasatinib capsule.
Stripping curve:
| |
1# | 2# | 3# | 4# | 5# | 6# | Average | SD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.00 | 0.00 | |
| 5 | 59.5 | 60.5 | 60.7 | 57.8 | 63.4 | 65.1 | 61.2 | 2.7 | |
| 10 | 78.9 | 79.3 | 82.1 | 80.5 | 85.4 | 86.3 | 82.1 | 3.1 | |
| 20 | 90.3 | 90.9 | 91.5 | 90.5 | 93.2 | 95.4 | 92.0 | 2.0 | |
| 30 | 95.6 | 97.1 | 97.9 | 94.3 | 97.6 | 98.4 | 96.8 | 1.6 | |
| 45 | 96.8 | 97.5 | 98.3 | 97.7 | 98.2 | 98.5 | 97.8 | 0.6 | |
| 60 | 97.3 | 98.2 | 96.9 | 97.9 | 98.5 | 98.8 | 97.9 | 0.7 |
| |
1# | 2# | 3# | 4# | 5# | 6# | Average | SD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.00 | 0.00 | |
| 5 | 57.9 | 61.1 | 63.4 | 59.8 | 63.9 | 55.3 | 60.2 | 3.3 | |
| 10 | 83.1 | 79.5 | 82.9 | 83.6 | 84.7 | 82.1 | 82.7 | 1.8 | |
| 20 | 91.4 | 95.3 | 94.2 | 90.7 | 93.8 | 93.3 | 93.1 | 1.7 | |
| 30 | 96.5 | 97.1 | 98.6 | 96.3 | 96.9 | 98.8 | 97.4 | 1.1 | |
| 45 | 98.5 | 96.9 | 98.8 | 98.6 | 97.9 | 98.4 | 98.2 | 0.7 | |
| 60 | 98.9 | 97.3 | 97.1 | 98.8 | 98.5 | 98.5 | 98.2 | 0.8 |
The prescription of Dasatinib tablet and preparation technology:
With several vehicle above-mentioned Dasatinib polymorph III is made the tablet that contains 50mg as follows.
The manufacture method that contains the tablet of Dasatinib polymorph III is that preceding four kinds in the above-mentioned vehicle are added water and make softwood in right amount with Dasatinib polymorph III, carry out drying after softwood made wet granular, dried particle and Magnesium Stearate mix the back compressed tablets, and the gained tablet is wrapped up in film-coat with Opadry dressing material package and promptly obtained the Dasatinib tablet.
Stripping curve:
| |
1# | 2# | 3# | 4# | 5# | 6# | Average | SD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.00 | 0.00 | |
| 5 | 43.2 | 48.4 | 40.7 | 45.7 | 44.2 | 45.8 | 44.7 | 2.6 | |
| 10 | 75.2 | 76.3 | 73.8 | 76.8 | 77.2 | 75.2 | 75.8 | 1.3 | |
| 20 | 87.3 | 89.5 | 86.8 | 90.7 | 86.3 | 88.9 | 88.3 | 1.7 | |
| 30 | 95.1 | 93.7 | 96.8 | 95.5 | 97.7 | 97.9 | 96.1 | 1.6 | |
| 45 | 98.5 | 97.9 | 97.6 | 98.1 | 99.2 | 98.1 | 98.2 | 0.6 | |
| 60 | 98.3 | 98.3 | 98.7 | 98.9 | 98.9 | 98.5 | 98.6 | 0.3 |
| |
1# | 2# | 3# | 4# | 5# | 6# | Average | SD％ | |
| 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0.00 | 0.00 | |
| 5 | 46.1 | 41.7 | 45.8 | 47.1 | 46.5 | 40.8 | 44.7 | 2.7 |
| 10 | 73.9 | 70.1 | 76.8 | 77.2 | 75.7 | 78.3 | 75.3 | 3.0 |
| 20 | 85.2 | 82.1 | 88.4 | 87.5 | 89.6 | 85.4 | 86.4 | 2.7 |
| 30 | 94.6 | 92.5 | 96.3 | 95.8 | 98.3 | 96.2 | 95.6 | 1.9 |
| 45 | 97.9 | 97.5 | 98.4 | 98.6 | 98.9 | 96.8 | 98.0 | 0.8 |
| 60 | 98.7 | 98.6 | 96.7 | 97.5 | 97.8 | 98.3 | 97.9 | 0.8 |
Can prepare capsule and the tablet that contains Dasatinib 20mg/70mg/80mg/100mg/140mg with method.
The stability simultaneous test:
Preparing Dasatinib polymorph A (being designated hereinafter simply as " 916.6 polymorphic form A ") with the disclosed method of CN200580011916.6 is representative, and the study on the stability method and the result of polymorphic form III of the present invention (being designated hereinafter simply as " polymorphic form III ") contrast breaking test:
Table 16 " 916.6 polymorphic form A " and polymorphic form III breaking test study on the stability result
Experimental technique:
Oxidation destroys: sample thief 50mg, and accurate the title, decide, and places the 100ml measuring bottle, adds 30% hydrogen peroxide 10ml, and room temperature was placed after 2 hours, was diluted to scale with moving phase, shook up, and high performance liquid chromatography detects.
Acid destroys: sample thief 50mg, and accurate the title, decide, and places the 100ml measuring bottle, the hydrochloric acid soln 10ml that adds 1mol/L after 1 hour, adds the sodium hydroxide solution neutralization of the 1mol/L of equivalent in 40 ℃ of placements, be diluted to scale with moving phase again, shake up, high performance liquid chromatography detects.
Alkali destroys: sample thief 50mg, and accurate the title, decide, and places the 100ml measuring bottle, the sodium hydroxide solution 10ml that adds 1mol/L after 1 hour, adds the hydrochloric acid soln neutralization of the 1mol/L of equivalent in 40 ℃ of placements, be diluted to scale with moving phase again, shake up, high performance liquid chromatography detects
Illumination destroys: sample thief 50mg, accurately claim surely, and place the 100ml measuring bottle, make the solution that every 1ml contains Dasatinib 0.5mg approximately with moving phase dissolving and dilution dilution, put under the 40001x illumination about 6 hours.High performance liquid chromatography detects.
High temperature destroys: sample thief 50mg, the accurate title, decide, and places the 100ml measuring bottle, makes the solution that every 1ml contains Dasatinib 0.5mg approximately with moving phase dissolving and dilution dilution, puts in 60 ℃ of waters bath with thermostatic control, takes out after about 4 hours, puts cold.High performance liquid chromatography detects.
The determination of related substances detection method:
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; (0.2% triethylamine is with phosphorus acid for adjusting pH value to 2.5)-methyl alcohol (45: 55) is moving phase with the 0.05mol/L potassium primary phosphate; Detect wavelength 230nm; Theoretical plate number is calculated by the Dasatinib peak should be not less than 2000.The resolution of Dasatinib peak and adjacent impurity peaks should meet the requirements.
The assay method sample thief adds the moving phase dissolving and makes the solution that contains 0.5mg among every 1ml, measures 20 μ l, injects liquid chromatograph respectively, and the record color atlas is to 6 times of principal constituent peak retention time.If any impurity peaks, press the peak area normalization method and calculate total assorted and single impurity in the need testing solution color atlas.
The stability of crystal formation in preparation
Detect the capsule of preparation in the embodiment of the invention 3 and 4 and the x-ray diffraction pattern of tablet, compare, be listed as follows with the XRPD of the Dasatinib polymorph III of the embodiment of the invention 1 preparation:
Comparing result data in the above-mentioned contrast table show that Dasatinib polymorph III of the present invention is after preparation process is made capsule or tablet, and its crystal formation remains unchanged substantially.
In addition, detect the capsule of preparation in the embodiment of the invention 3 and 4 and the related substance of tablet, compare, be listed as follows with the related substance of the Dasatinib polymorph III of the embodiment of the invention 1 preparation:
Comparing result data in the above-mentioned contrast table show that Dasatinib polymorph III of the present invention is after preparation process is made capsule or tablet, and Dasatinib polymorph III is stable, and related substance does not have obvious variation.
Claims (9)
1. the polymorphic form of Dasatinib monohydrate uses the Cu-Ka radiation, and in its x-ray diffraction pattern, 2 θ that show with kilsyth basalt are 9.1 ± 0.1, and 27.9 ± 0.1, and there is diffraction peak at 28.5 ± 0.1 places.
2. polymorphic form according to claim 1, in its x-ray diffraction pattern, 2 θ that show with kilsyth basalt are 9.1 ± 0.1,11.1 ± 0.1,13.7 ± 0.1,15.1 ± 0.1,17.9 ± 0.1,18.3 ± 0.1,19.1 ± 0.1,19.5 ± 0.1,22.2 ± 0.1,23.1 ± 0.1,23.5 ± 0.1,24.3 there is diffraction peak at ± 0.1,25.8 ± 0.1,27.9 ± 0.1 and 28.5 ± 0.1 places.
3. polymorphic form according to claim 2 uses the Cu-Ka radiation, has following diffraction peak in its x-ray diffraction pattern:
4. polymorphic form according to claim 2, its x-ray diffraction pattern as shown in Figure 1.
5. according to the described polymorphic form of arbitrary claim in the claim 1 to 4, its DSC scanning particularly has first endotherm(ic)peak about 122 ℃ between 80～130 ℃; Between 280～285 ℃, particularly second endotherm(ic)peak is arranged about 281 ℃.
6. according to the described polymorphic form of arbitrary claim in the claim 1 to 4,, it is characterized by at about 3464.39cm with the infrared absorption pattern that the KBr compressing tablet records
-1, 3211.60cm
-1, 3013.97cm
-1, 2954.56cm
-1, 2824.32cm
-1, 1682.81cm
-1, 1634.18cm
-1, 1612.84cm
-1, 1584.72cm
-1, 1305.92cm
-1, 1291.54cm
-1, 1041.40cm
-1, and 1000.46cm
-1There is absorption peak at the place.
7. the preparation method of the described polymorphic form of arbitrary claim in the claim 1 to 6 comprises the steps:
(1) Dasatinib is added in the entry; Wherein: the volume of water and Dasatinib and weight ratio were greater than 1: 1;
(2) heating under agitation; Heating temperature is that room temperature is to reflux temperature;
(3) insulation growing the grain; Rearing crystal time was at 10 minutes to 72 hours;
(4) reduce to the room temperature solid collected by filtration, and dry.
8. preparation method according to claim 7, wherein,
In the step (1), the volume of water and Dasatinib and weight ratio were more than or equal to 5: 1; Most preferably, the volume of water and Dasatinib and weight ratio are 5: 1 to 15: 1;
In the step (2), Heating temperature be 40 ℃ to reflux temperature; Most preferably be selected from: Heating temperature be 80 ℃ to reflux temperature;
In the step (3), rearing crystal time is 1 hour to 48 hours; Most preferably be 2 hours to 6 hours.
9. pharmaceutical composition that comprises the described polymorphic form of arbitrary claim in the claim 1 to 6.
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| US20120309968A1 (en) * | 2010-02-08 | 2012-12-06 | Nan Jing Cavendish Bio-Engineering Technology Co., Ltd. | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof |
| CN102898424A (en) * | 2011-07-29 | 2013-01-30 | 江苏奥赛康药业股份有限公司 | Novel polymorphs of dasatinib, and preparation method thereof |
| CN103059013A (en) * | 2011-10-18 | 2013-04-24 | 北京本草天源药物研究院 | New crystal of Dasatinib monohydrate and preparation method thereof |
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| CN111108104A (en) * | 2017-07-07 | 2020-05-05 | 拜康有限公司 | Polymorphic forms of dasatinib |
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