CN102816145A - Methanesulfonic acid imatinib polymorphic substance and medical combination thereof - Google Patents

Abstract

The invention discloses methanesulfonic acid imatinib polymorphic substance III. In addition, the invention further discloses a preparation and medical combination of the methanesulfonic acid imatinib polymorphic substance III.

Description

STI571 polymorphic form and medicinal compsns thereof

Technical field

The present invention relates to the polymorphic form of medical compounds, more particularly, relate to a kind of polymorphic form of novel STI571, in addition, the invention still further relates to the preparation method and the pharmaceutical composition thereof of this polymorphic form.

Background technology

STI571 is a kind of tyrosinase inhibitor, is used to treat gi tract Leydig's cell tumor (GISTs).Its chemical name is 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-the BM mesylate, chemical structure is following:

One Chinese patent application-application number 98807303.X (hereinafter to be referred as No. 303, patented claim) discloses the two kinds of polymorphic form α and the β of STI571; Wherein, the characteristic of alpha-crystal form is to have water absorbability, mobile bad needle crystal, and its typical X RPD collection of illustrative plates shows the α type 4.9,10.5,14.9,16.5; 17.7,18.1,18,6,19.1,21.3,21.6; 22.7 there is the peak at 23.2,23.8,24.9,27.4,28.0 and 28.6 ± 0.1 degree, 2 θ places.

The beta crystal characteristic of this patent documentation record is:, good fluidity little at Thermodynamically stable below 140 ℃, water absorbability, be easy to the non-needle crystal of storing and processing.These characteristics are all to the preparation of preparation and store useful; 9.7,13.9, there is the peak at 14.7,17.5,18.2,20.0,20.6,21.1,22.1,22.7,23.8,29.8 and 30.8 ± 0.1 degree, 2 θ places; And the preparation method of its polycrystalline thing is provided.The preparation method who provides in this document is following:

Alpha crystalline form: with 98.6g (0.2mol) free 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl]-BM (preparation is referring to EP-A-0564409) joins in 1.4 liters of ethanol.In this cream-coloured suspension-s, with 20 minutes dropping 19.2g (0.2mol) methylsulfonic acids.With this vlil 20 minutes, and then 65 ℃ of following filterings.Filtrating is evaporated 50%, and residue filters (strainer material A) under 25 ℃.Mother liquid evaporation is extremely done.Residue and strainer material A are suspended in 2.2 liters of ethanol and add the dissolving that refluxes of 30ml water.Cool overnight to 25 ℃, filter and 65 ℃ of dryings until constant weight.Obtain 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl of oldlace]-crystallization of BM mesylate.

Beta-crystalline form:

Method 1: with 4-(4-N-METHYL PIPERAZINE-1-the methyl)-N-of 11% (w/w) α-crystalline form [4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-BM mesylate suspension-s in methyl alcohol about 25 ℃ of dippings 2 days.Filtering separation crystallization on the G4 glass filter, at room temperature dried overnight on filter paper.

Method 2: with 50.0g (101mmol) 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl]-the BM mesylate is suspended in the methyl alcohol (480ml).Add 9.71g (101mmol) methylsulfonic acid and methyl alcohol (20ml), be heated to 50 ℃, add gac (5.0), this mixture was seethed with excitement 30 minutes under refluxing, filter and evaporation concentration.Resistates is dissolved in methyl alcohol (150ml), inoculation 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl]-BM mesylate (β variant, several milligrams), cause the product crystallization.Dry down at 50 person of outstanding talent crust with 60 ℃, obtain 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl of β variant]-the BM mesylate.

Method 3: with 670g (1136mmol) 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl]-BM mesylate (α-variant) heats in methyl alcohol (1680ml).In this solution, inoculate 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-is amino] phenyl down at 60 ℃]-BM mesylate (β variant, 55 milligrams), this moment, product began crystallization.Dry down at 50 person of outstanding talent crust with 100 ℃, obtain 4-(4-N-METHYL PIPERAZINE-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidine-2-amino] phenyl of β variant]-the BM mesylate.

In addition, at patent WO2006/024863, WO2005/077933, CN200680030515.X, 200680044007.7 disclose the crystallized form of the STI571 of stable α, α 2, δ, ε, F, G, H, I and K type.

More than disclosed crystallization method all be that imatinib is suspended in the organic solvent crystallized form that directly obtains with the methylsulfonic acid salify; Or STI571 is suspended in the solvent under certain temperature, adds or do not add crystal seed and change brilliant and obtain.It is loaded down with trivial details that existing these methods exist technology, and circulation ratio is unstable, and technical scheme can't guarantee effectively to remove mechanical impurity, and technical scheme can cause the residual genetoxic impurity risk that exists in the product, is not suitable for the serial shortcoming of suitability for industrialized production and product purity difference.

For the polymorphic of medicine, different polymorphics can have different chemistry and physical property, comprises fusing point, chemicalstability, apparent solubility, dissolution rate, optics and mechanical properties, vp 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 prepn.

For STI571; This area exists such demand: be suitable for commercial scale prodn, product gas purity is high, contains genetoxic impurity anything but; The physicochemical property excellence, can effectively apply to the novel polymorphic medicine that medication preparation and list marketing are used.

Summary of the invention

The contriver has been surprisingly found out that a kind of new STI571 polymorphic form through a large amount of research, has successfully solved the deficiency that prior art exists; And polymorphic form of the present invention possesses simultaneously: product gas purity is high, contains genetoxic impurity anything but; Physico-chemical property is excellent; Good stability is more suitable for the industrially scalable preparation, can effectively apply to the advantages such as novel polymorphic medicine that medication preparation and list marketing are used.

The STI571 polymorphic form III that the purpose of this invention is to provide novelty with above-mentioned technological merit.

Another object of the present invention provides the preparation method of the novel polymorphic thing III with above-mentioned technological merit.

The 3rd purpose of the present invention provides the medicinal compsns with containing of above-mentioned technological merit above-mentioned novel polymorphic thing III.

Specifically, the invention provides a kind of STI571 polymorphic form III that is substantially free of solvent (organic solvent or water).

The polymorphic form III of STI571 provided by the present invention; Use the Cu-Ka radiation; Typical X-x ray diffration pattern x that it is multiple batches of; 2 θ that show with kilsyth basalt have diffraction peak 5.9 ± 0.2,17.1 ± 0.2 and 24.2 ± 0.2; Particularly diffraction peak is arranged, see Fig. 1 at 5.9 ± 0.2,9.5 ± 0.2,12.8 ± 0.2,14.0 ± 0.2,15.1 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.7 ± 0.2,20.8 ± 0.2,23.2 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,25.1 ± 0.2,28.3 ± 0.2 places.The polymorphic form III of STI571 provided by the present invention; Use the Cu-Ka radiation; Typical X-x ray diffration pattern x that it is multiple batches of; 2 θ that show with kilsyth basalt have diffraction peak at 5.9 ± 0.2,9.5 ± 0.2,12.8 ± 0.2,14.0 ± 0.2,15.1 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.7 ± 0.2,20.8 ± 0.2,23.2 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,25.1 ± 0.2,28.3 ± 0.2 places, and the relative intensity of these diffraction peaks (I/IO) is greater than 20.

The polymorphic form III of STI571

The peak numbering	2θ	The Flex width	The d-value	Intensity	I/IO
						1	5.940	0.259	14.8665	3109	73
2	9.500	0.282	9.3020	1085	26
						3	11.220	0.212	7.8796	530	13
4	11.960	0.259	7.3937	927	22
						5	12.780	0.259	6.9210	1763	42
6	13.440	0.235	6.5826	874	21
						7	13.980	0.282	6.3295	1973	47
8	15.120	0.235	5.8548	1659	39
						9	15.520	0.212	5.7048	1471	35
10	15.840	0.235	5.5902	1592	38
						11	17.060	0.282	5.1931	4011	94
12	18.020	0.259	4.9186	3448	81
						13	18.620	0.235	4.7614	3299	78
14	19.080	0.329	4.6476	2521	59
						15	19.700	0.282	4.5027	3503	82
16	20.840	0.282	4.2589	3807	89

17	22.080	0.376	4.0225	1640	39
						18	22.660	0.212	3.9208	1526	36
19	23.200	0.329	3.8308	2072	49
						20	23.720	0.259	3.7479	3223	76
21	24.160	0.282	3.6807	4282	100
						22	25.120	0.282	3.5421	2518	59
23	25.900	0.282	3.4372	1201	29
						24	28.280	0.306	3.1531	1665	39
25	28.840	0.235	3.0932	1153	27
						26	29.060	0.235	3.0702	1248	30
27	30.320	0.471	2.9455	859	21
						28	30.880	0.212	2.8933	799	19

STI571 polymorphic form III provided by the present invention, through the organic residue detection of gas phase, acetone and methyl ethyl ketone do not detect, and the MTBE residual quantity is below 0.2%.Organic residual limit that meets ICH require (the MTBE limit: 0.5%, the acetone limit: 0.5%, methyl ethyl ketone limit: 0.5%); Through its moisture value of Ka Shi water content detection is below 0.5%.The above results shows that STI571 polymorphic form III provided by the present invention is more suitable for medicinal requirement.

In embodiments of the invention, the invention provides the preparation method of STI571 polymorphic form III, this method comprises the step of following order:

(1) imatinib is added in MTBE and the methylsulfonic acid, stir reaction down, obtain STI571; Here, preferably, the envelope-bulk to weight ratio of MTBE and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1; Preferably, the insulated and stirred reaction is 1～10 hour under room temperature to the arbitrary temp that refluxes, more preferably, and insulated and stirred reaction under refluxad 2 hours;

(2) stirred following cooling crystallization 0.5 to 10 hour; Preferably, be cooled to room temperature; Preferably, the crystallization time is 1～5 hour;

(3) suction filtration;

(4) collect the filter cake that obtains, decompression is dry down; Preferably, in room temperature～80 ℃, drying under reduced pressure promptly obtains STI571 polymorphic form III to constant weight.

In the preparation method of above-mentioned STI571 polymorphic form III provided by the invention, wherein, the imatinib that uses in the step (1) adopts the EP-A-0564409 preparation, preferably prepares through following mode:

The STI571 bullion is added in the entry dissolving under agitation or under agitation be warming up to dissolving; Suction filtration, filtrating is reduced to room temperature, stirs to add insoluble with imatinib or sl. sol. organic solvent down; Then, adding and STI571 bullion be a kind of alkali of equimolar amount at least, makes imatinib free fully; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake are used suitable quantity of water drip washing, take out filtration cakes torrefaction and obtain imatinib.Here, said insoluble with imatinib or sl. sol. organic solvent is a kind of in acetone or the methyl ethyl ketone, perhaps their mixture; And the volume ratio of organic solvent and water is 1: 5-100; Described a kind of alkali is alkali-metal carbonate or supercarbonate, more preferably, is yellow soda ash or sodium hydrogencarbonate, preferably preferably, is sodium hydrogencarbonate.

In the preparation method of STI571 polymorphic form III of the present invention, said STI571 bullion can be prepared by existing method, for example; But be not limited to following patent CN98807303.X, WO2006/024863, WO2005/077933; CN200680030515.X; CN200680044007.7 obtains among the CN201010286254.6, perhaps the STI571 bullion of their α, α 2, δ, ε, F, G, H, I and K type.At this, these documents are introduced here as a reference with its full content.

As a kind of embodiment preferred, the invention provides the preparation method of a kind of STI571 polymorphic form III, comprise the steps:

(1) imatinib is added in MTBE and the methylsulfonic acid, stir reaction down, obtain STI571; Here, preferably, the envelope-bulk to weight ratio of MTBE and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1; Preferably, the insulated and stirred reaction is 1～10 hour under room temperature to the arbitrary temp that refluxes, more preferably, and insulated and stirred reaction under refluxad 2 hours;

(2) stirred following cooling crystallization 0.5 to 10 hour; Preferably, be cooled to room temperature; Preferably, the crystallization time is 1～5 hour;

(3) suction filtration;

(4) collect the filter cake that obtains, decompression is dry down; Preferably, in room temperature～80 ℃, drying under reduced pressure promptly obtains STI571 polymorphic form III to constant weight;

Here, the imatinib that said step (1) is used prepare through following method: the STI571 bullion is added in the entry, under agitation dissolve or under agitation be warming up to dissolving; Suction filtration, filtrating is reduced to room temperature, stirs to add insoluble with imatinib or sl. sol. organic solvent down; Then, adding and STI571 bullion be a kind of alkali of equimolar amount at least, makes imatinib free fully; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake are used suitable quantity of water drip washing, take out filtration cakes torrefaction and obtain imatinib.Here, said insoluble with imatinib or sl. sol. organic solvent is a kind of in acetone or the methyl ethyl ketone, perhaps their mixture; And the volume ratio of organic solvent and water was greater than 1: 5; Described a kind of alkali is alkali-metal carbonate or supercarbonate, more preferably, is yellow soda ash or sodium hydrogencarbonate, preferably preferably, is sodium hydrogencarbonate.

As a kind of particularly preferred embodiment, the invention provides the preparation method of a kind of STI571 polymorphic form III, comprise the steps:

(1) imatinib is added in MTBE and the methylsulfonic acid, insulated and stirred reaction under refluxad 1-10 hour is more preferably reacted 2 hours, thereby is obtained STI571; Here, the envelope-bulk to weight ratio of MTBE and imatinib is 5～20: 1, more preferably 10～15: 1; And the mol ratio of methylsulfonic acid and imatinib is 1: 1;

(2) be cooled to room temperature, crystallization 1～5 hour under the stirring;

(3) suction filtration;

(4) collect the filter cake obtain, in room temperature～80 ℃, drying under reduced pressure promptly obtains STI571 polymorphic form III to constant weight;

Here, the imatinib that said step (1) is used prepare through following method: the STI571 bullion is added in the entry, under agitation dissolve or under agitation be warming up to dissolving; Suction filtration, filtrating is reduced to room temperature, stirs to add acetone or methyl ethyl ketone or their mixture down; Then, adding and STI571 bullion be the sodium hydrogencarbonate of equimolar amount at least, makes imatinib free fully; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake are used suitable quantity of water drip washing, take out filtration cakes torrefaction and obtain imatinib.Here, the volume ratio of acetone or methyl ethyl ketone or their mixture and water was greater than 1: 5.

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 limit that copper target, graphite monochromator, tube voltage 40kv, tube current 100mA, divergent slit and anti-scatter slit are 1 °, reception slit.Instrument is corrected through the silicon-dioxide standard substance.

STI571 content involved in the present invention and related substance testing conditions: measure according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2005).

The condition of HPLC:

Chromatographic column: use the octadecylsilane chemically bonded silica of improvement to be weighting agent.

Eluent (gradient): 0%b) in a), 20 minutes, 0% → 30%b) in a) then, and 10 minutes, 30%b then) in a), 5 minutes.

Eluent is a): 1% perfluoroetane sulfonic acid sodium solution (pH2.5): methyl alcohol (42: 58)

Eluent b): 1% perfluoroetane sulfonic acid sodium solution (pH2.5): methyl alcohol (4: 96)

Detect wavelength: 267nm

Flow velocity: 1.2ml/min

Column temperature: 25 ℃.

The characteristic of STI571 polymorphic form III

One, solubility experiment:

Method: it is an amount of that precision takes by weighing STI571 polymorphic form III, slowly adds a certain amount of dissolve medium, and the dissolving situation in 30 minutes is observed in every powerful jolting 30 seconds at a distance from 5 minutes, and the result sees table 1.

The solubility test of table 1 STI571 polymorphic form III

What the imatinib mesylate bulk drug that has gone on the market adopted is beta crystal, and described the solvability of STI571 above that in city's specification sheets: " STI571 is dissolved in the buffered soln of pH≤5.5; Atomic dissolving to being insoluble to neutrality/alkaline water buffered soln; Be soluble in to being slightly soluble in methyl-sulphoxide, in methyl alcohol and the ethanol; Be insoluble to n-Octanol, in acetone and the acetonitrile ".Above-mentioned solubility experiment shows that STI571 polymorphic form III solvability in each solvent obviously is superior to the crystal formation that goes on the market.

Two, stability

1, exposure experiments to light

STI571 polymorphic form III is evenly shared to uncovered petridish, 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 result sees table 2.

Table 2 exposure experiments to light (4500 ± 500lx)

Annotate: range of temperature is 23～26 ℃; The relative humidity variations scope is 58%～63%

2, high temperature test

STI571 polymorphic form 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 result sees table 3.

Table 3 high temperature test (60 ℃)

Annotate: the relative humidity variations scope is 53%～61%

3, accelerated test

The raw material of STI571 polymorphic form III is packed with the polyvinylidene 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 result sees table 4.

Table 4 accelerated test (40 ℃, relative humidity 75%)

Can know by The above results, the STI571 polymorphic form III that the present invention obtains, its outward appearance, related substance and content all do not have obvious change in exposure experiments to light and high temperature test (60 ℃), explain that its physico-chemical property is relatively stable; These article are not observed crystal formation and are changed in long-term reserved sample observing test.

Above-mentioned experiment shows that the crystal habit of polymorphic form III of the present invention is relatively stable, is suitable for processing medicine and preparation thereof.

In another embodiment of the invention; The invention provides the medicinal compsns that contains above-mentioned STI571 polymorphic form III and pharmaceutical excipient; Preferably; It is the 1-1000 milligram that this medicinal compsns unit formulation contains STI571 polymorphic form III, particularly preferably, contains about 50,100,200,400 milligrams of above-mentioned STI571 polymorphic form III.According to the instruction of state of the art, and with reference to the patent that the present invention quoted, medicinal compsns of the present invention can be made into various formulations, and selects suitable pharmaceutical excipient.For example; According to waiting to treat disease and object; Medicinal compsns of the present invention, administered through 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 parenteral (for example intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or perfusion, subcutaneous injection or perfusion) preparation, for example formulation such as freeze-dried prepn, injection.

The present invention comprises the medicinal compsns of STI571 polymorphic form III, optionally also can contain other therapeutic component.

Medicinal compsns of the present invention is once a day or repeatedly per daily dose and administration, and per daily dose is about the 1-2500 mg/day, more preferably about 1-1000 mg/day.

The example that STI571 polymorphic form III of the present invention can be used for treating disease and symptom includes but not limited to: diseases such as treatment myeloproliferative disease, osteomyelodysplasia syndromes, vasculogenesis, cancer, pain, degeneration of macula, osteomyelodysplasia syndromes, asbestosis, anemia, nervous system disorders, dyssomnia, tetter, pulmonary hypertension, immune deficiency disorder, management of parasitic diseases, central nervous system injury.

Useful technique effect of the present invention is embodied in: although prior art-patented claim discloses STI571 α and beta crystal thing and preparation method thereof for No. 303, the method for the polymorphic form of the preparation STI571 of No. 303 instructions of patented claim is not suitable for the needs of mass-producing stably manufactured.

The preparation method that No. 303, patented claim is under 20 ℃～50 ℃ temperature; The added methanesulfonic acid salify raw material suspension of another kind of crystalline form or amorphous formula I compound impregnated in a kind of suitable polar solvent; Perhaps with the another kind of crystal formation of STI571; Under the suitable temp of backflow 6 temperature of 25 ℃～reaction mixture, be dissolved in a kind of polar solvent, add β-crystalline forms down at 20 ℃～70 ℃ then and cause crystallization as crystal seed.

1, the beta crystal that in No. 303, patented claim, provides, though on physico-chemical property, better be fit to medicinally, the preparation method is complicated, needs to add crystal seed and causes, or adopted and can cause that the solvent of genetoxic impurity prepares.

2, all technical schemes of providing for No. 303 of patented claim all can not effectively be removed impurity, and product purity is low.

In a word, in patented claim 303 and the prior art STI571 polymorphic form have such as: can't avoid genetoxic impurity, poor stability, the mobile difference of crystal formation waits and is unfavorable for medicinal shortcoming; Or complex process, complex operation, poor repeatability, defective workmanship such as product purity is low is so existing STI571 polymorphic form or its preparation technology are all not ideal enough.

Yet; STI571 polymorphic form III provided by the invention, its preparation technology is simple, and the product gas purity for preparing is high; Definitely avoid genetoxic impurity; The physico-chemical property good stability, the STI571 polymorphic form and the preparation method of suitable suitability for industrialized production have overcome the various defect problems that exist in the prior art.

The present invention is to the polymorphic form of STI571, 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, and yield is high, and technology collimation and favorable reproducibility are fit to technology production;

2, the prepared polymorphic form solvability of preparation technology of the present invention, stability, physico-chemical property excellence are suitable for medicinal;

3, polymorphous preparation method of the present invention can effectively remove mechanical impurity.

4, optionally use the non-alcohols of low toxicity and three kind solvents of ester class among polymorphous preparation method of the present invention.Avoid generating alkyl sulfonates genetoxic impurity.This has played success or failure and conclusive effect to reality of the present invention is medicinal.

5, the preparation method of polymorphic form of the present invention optionally uses three kind solvents of low toxicity.Because it is easy to form solvolyte the decision of this structural compounds textural property, the organic solvent that this present invention selects then can effectively be avoided forming solvolyte with this structural compounds.Be more suitable in medicinal.

6, polymorphous preparation method of the present invention can effectively remove impurity, and particularly strong polar impurity can obtain the high-purity STI571 up to 99.9%.

7, tablet that is prepared by polymorphic form of the present invention and capsule contrast crystal formation (β type) and have more excellent dissulution, are more suitable for medicinal.

Above advantage shows, the present invention is of value to the quality of product significantly improved and be more suitable for suitability for industrialized production.

Description of drawings

Fig. 1 is the typical X RPD figure of STI571 polymorphic form III of the present invention.

Fig. 2 is the color atlas of the STI571 polymorphic form III for preparing of the embodiment of the invention 1.

Peak #	RT	Area %
			1	2.930	0.009
2	4.866	0.023
			3	10.783	0.055
4	14.093	99.867
			5	23.216	0.010
6	29.365	0.036

Embodiment

The preparation of embodiment 1 STI571 bullion

With imatinib (2Kg), methylsulfonic acid (390g) and acetone (20L) add in the reaction flask, are warming up to back flow reaction 2.5 hours under stirring.Reduce to room temperature, stirring and crystallizing 3 hours.Suction filtration, the filter cake that collection obtains to constant weight, get STI571 bullion 2.2Kg in 70 ℃ of drying under reduced pressure.Yield, 92.1%.

Purity: 98.7%.

The preparation of embodiment 2 polymorphic form III

Preparation imatinib free alkali

The STI571 bullion (1.5Kg) that embodiment 1 is obtained adds in the entry (15L), is warming up to 60 ℃, stirring and dissolving.The suction filtration removal of impurities.Filtrating is reduced to room temperature, stirs to add acetone (4.5L) down.Add sodium hydrogencarbonate (214g), room temperature crystallization 3 hours.Suction filtration, filter cake washing after drying to constant weight obtains imatinib 1.17Kg.Yield: 92.9%.

The preparation STI571

With the above-mentioned imatinib that obtains (80g), methylsulfonic acid (15.6g) and MTBE (800ml) add in the reaction flask, are warming up to back flow reaction 2 hours under stirring.Reduce to room temperature, stirring and crystallizing 1 hour.Suction filtration, the filter cake that collection obtains to constant weight, get STI571 polymorphic form III 87.6g, yield, 91.6% in 70 ℃ of drying under reduced pressure.

Purity: 99.87% (see figure 2).

Organic residual: acetone-do not detect (limit: 0.50%); MTBE-0.15% (limit: 0.50%).

The preparation of embodiment 3 polymorphic form III

We are according to existing method, and the STI571 of the different crystal forms for preparing with different process is a raw material, and it is following to adopt embodiment 2 schemes to prepare the data list of polymorphic form III:

Visible by above-mentioned testing data, the STI571 bullion of crystal formation all can be converted into crystal formation of the present invention arbitrarily.Simultaneously, can effectively remove impurity, obtain high-purity STI571 up to 99.9%.

The preparation of embodiment 4 polymorphic form III

Preparation imatinib free alkali

STI571 bullion (100g) is added in the entry (1L), be warming up to 60 ℃, stirring and dissolving.The suction filtration removal of impurities.Filtrating is reduced to room temperature, stirs to add methyl ethyl ketone (450ml) down.Add sodium hydrogencarbonate (14.2g), room temperature crystallization 2.5 hours.Suction filtration, filter cake washing after drying to constant weight obtains imatinib 75.6g.Yield: 90.3%.

The preparation STI571

With the above-mentioned imatinib that obtains (20g), methylsulfonic acid (3.9g) and MTBE (250mL) add in the reaction flask, are warming up to back flow reaction 2 hours under stirring.Reduce to room temperature, stirring and crystallizing 1 hour.Suction filtration, the filter cake that collection obtains to constant weight, get STI571 polymorphic form III 21.6g, yield, 90.4% in 70 ℃ of drying under reduced pressure.

Purity: 99.89%.

Organic residual: acetone-do not detect (limit: 0.5%), methyl ethyl ketone-do not detect (limit: 0.5%), MTBE-0.12%.

The preparation of embodiment 5 polymorphic form III

We are according to existing method, and the STI571 of the different crystal forms for preparing with different process is a raw material, and it is following to adopt embodiment 4 schemes to prepare the data list of polymorphic form III:

Visible by above-mentioned testing data, the STI571 bullion of crystal formation all can be converted into crystal formation of the present invention arbitrarily.Simultaneously, can effectively remove impurity, obtain high-purity STI571 up to 99.9%.

The prescription and the preparation technology of embodiment 6 STI571 tablets:

With several kinds of vehicle above-mentioned STI571 polymorphic form III is processed the tablet that contains 100mg as follows.

STI571 (in imatinib)	100g
		Microcrystalline Cellulose	40g
Hypromellose	2g
		PVPP	15g
Micropowder silica gel	13g
		Magnesium Stearate	1.5g
Compacting	1000

Take by weighing Microcrystalline Cellulose, hypromellose and PVPP by prescription, mix, get the auxiliary material powder, subsequent use.Take by weighing STI571 by prescription, mix, get the pastille mixed powder with the auxiliary material powder.It is an amount of to add water to the pastille mixed powder, the system wet granular, and the whole grain in dry back adds micropowder silica gel and Magnesium Stearate, with dried particle mixing, is pressed into tablet.

No. 303 beta crystal bulk drugs of patented claim by above-mentioned prescription and technology, are prepared into tablet equally and measure dissulution.

Dissolution determination method: with the 0.1mol/L hydrochloric acid soln is dissolution medium, measures according to dissolution method (2010 editions two appendix XC second methods of Chinese Pharmacopoeia).

Dissolution data compares:

Dissolution time	Crystal form II I dissulution	The brilliant dissulution of No. 303 β of patented claim
			10 minutes	84％	73％
15 minutes	92％	82％

Capsular prescription of embodiment 7 STI571s and preparation technology:

With several kinds of vehicle above-mentioned STI571 polymorphic form III is processed the capsule that contains 100mg as follows.

STI571 (in imatinib)	100g
		Microcrystalline Cellulose	40g
PVPP	15g
		Micropowder silica gel	15g
Magnesium Stearate	1.5g
		Fill	1000 capsules

Take by weighing Microcrystalline Cellulose, PVPP, micropowder silica gel and Magnesium Stearate by prescription, mix, get the auxiliary material powder.Take by weighing STI571 by prescription, mix, get the pastille mixed powder with the auxiliary material powder.The pastille mixed powder is filled in No. 00 hard capsule makes capsule.

No. 303 beta crystal bulk drugs of patented claim by above-mentioned prescription and technology, are prepared into capsule equally and measure dissulution.

Dissolution determination method: with the 0.1mol/L hydrochloric acid soln is dissolution medium, measures according to dissolution method (2010 editions two appendix XC second methods of Chinese Pharmacopoeia).

Dissolution data compares:

Dissolution time	Crystal form II I capsule dissulution	No. 303 beta crystal capsules of patented claim dissulution
			10 minutes	80％	73％
15 minutes	89％	82％
			20 minutes	93％	85％

Although all meeting the requirements with the capsular dissulution of crystal formation of the present invention of No. 303 beta crystal capsules of patented claim dissulution, visible from above-mentioned correlation data, crystal formation of the present invention obviously is superior to beta crystal in medicinal properties, is more suitable in medicinal.

Claims (10)

1. the polymorphic form III of a STI571 uses the Cu-Ka radiation, its x-ray diffraction pattern, and 2 θ that show with kilsyth basalt have diffraction peak at 5.9 ± 0.2,17.1 ± 0.2 and 24.2 ± 0.2 places.

2. polymorphic form III according to claim 1; Its x-ray diffraction pattern, 2 θ that show with kilsyth basalt also have diffraction peak at 5.9 ± 0.2,9.5 ± 0.2,12.8 ± 0.2,14.0 ± 0.2,15.1 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,17.1 ± 0.2,18.0 ± 0.2,18.6 ± 0.2,19.1 ± 0.2,19.7 ± 0.2,20.8 ± 0.2,23.2 ± 0.2,23.7 ± 0.2,24.2 ± 0.2,25.1 ± 0.2,28.3 ± 0.2 places.

3. polymorphic form III according to claim 2, wherein, the relative intensity of described diffraction peak is greater than 20.

4. it is residual that the said polymorphic form III of arbitrary claim in the claim 1 to 3, the organic residue detection collection of illustrative plates of its vapor detection can detect methyl ethyl ketone, MTBE or the acetone of tracer level.

5. pharmaceutical composition that comprises the said polymorphic form III of arbitrary claim in the claim 1 to 4.

6. the preparation method of the said polymorphic form III of arbitrary claim in the claim 1 to 4, this method comprises the step of following order:

(1) imatinib is added in MTBE and the methylsulfonic acid, stir reaction down, obtain STI571; Here; And the mol ratio of methylsulfonic acid and imatinib is 1: 1;

(2) stirred following cooling crystallization 0.5 to 10 hour;

(3) suction filtration;

(4) collect the filter cake that obtains, be drying to obtain STI571 polymorphic form III under the decompression.

7. preparation method according to claim 6, wherein, the envelope-bulk to weight ratio of MTBE and imatinib is 5～20: 1 in the step (1), more preferably 10～15: 1.

8. preparation method according to claim 6, wherein, insulated and stirred reaction 1～10 hour under room temperature to the arbitrary temp that refluxes in the step (1), more preferably, insulated and stirred reaction under refluxad 2 hours.

9. preparation method according to claim 6, wherein, step (2) is cooled to room temperature under stirring, and the crystallization time is 1～5 hour; Step (4) is in room temperature～80 ℃, and drying under reduced pressure is to constant weight.

10. according to the described preparation method of arbitrary claim in the claim 6 to 9, wherein, the imatinib that uses in the step (1) prepares through following mode:

The STI571 bullion is added in the entry dissolving under agitation or under agitation be warming up to dissolving; Suction filtration, filtrating is reduced to room temperature, stirs to add insoluble with imatinib or sl. sol. organic solvent down; Then, adding and STI571 bullion be a kind of alkali of equimolar amount at least, makes imatinib free fully; And in room temperature crystallization 1-3 hour; Suction filtration, filter cake are used suitable quantity of water drip washing, take out filtration cakes torrefaction and obtain imatinib.Here, said insoluble with imatinib or sl. sol. organic solvent is a kind of in acetone or the methyl ethyl ketone, perhaps their mixture; And the volume ratio of organic solvent and water is 1: 5-100; Described a kind of alkali is alkali-metal carbonate or supercarbonate, more preferably, is yellow soda ash or sodium hydrogencarbonate, most preferably, is sodium hydrogencarbonate.

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